Combination therapy

ABSTRACT

Provided herein are methods of treating diseases, such as cancer, using a combination therapy. In certain embodiments, the methods comprise administering an effective amount of a phosphoinositide-3-kinase (PI3K) inhibitor and an effective amount of a CD20 inhibitor to a patient.

CROSS-REFERENCE

This application is a national stage entry of PCT/US2018/046742, filedon Aug. 14, 2018, and claims benefit of U.S. Patent Application No.62/545,427, filed on Aug. 14, 2017, which are all hereby incorporated byreference in their entirety.

BACKGROUND OF THE INVENTION

Phosphoinositide-3-kinases (PI3Ks) play a variety of roles in normaltissue physiology, with p110α having a specific role in cancer growth,p110β in thrombus formation mediated by integrin α_(II)β, and p110γ, ininflammation, rheumatoid arthritis, and other chronic inflammationstates. Inhibitors of PI3K have therapeutic potential in the treatmentof various proliferative diseases, including cancer.

SUMMARY OF THE INVENTION

Disclosed herein is a method for treating or preventing a diseasecomprising administering:

(i) an effective amount of a compound of Formula (I);

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

-   X, Y, and Z are each independently N or CR^(X), with the proviso    that at least two of X, Y, and Z are nitrogen atoms; where R^(X) is    hydrogen or C₁₋₆ alkyl;-   R¹ and R² are each independently (a) hydrogen, cyano, halo, or    nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,    C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),    —S(C)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a),    R^(1b), R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,    C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(1b) and    R^(1c) together with the N atom to which they are attached form    heterocyclyl;-   R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and    R⁴ are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆    heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;-   R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or    —(CR^(5f)R^(5g))_(n)-heteroaryl;-   R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one    occurrence of R^(5f) and one occurrence of R^(5g) are attached to    the same carbon atom, the R^(5f) and R^(5g) together with the carbon    atom to which they are attached form a C₃₋₁₀ cycloalkyl or    heterocyclyl;-   R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or    —SO₂—C₁₋₆ alkyl;-   m is 0 or 1; and-   n is 0, 1, 2, 3, or 4;-   wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,    heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl,    and heterocyclyl in R¹, R², R³, R⁴, R⁶, R^(X), R^(1a), R^(1b),    R^(1c), R^(1d), R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), and    R^(5g) is optionally substituted with one, two, three, four, or five    substituents Q, wherein each substituent Q is independently selected    from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,    heteroaryl, and heterocyclyl, each of which is further optionally    substituted with one, two, three, or four, substituents Q^(a);    and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),    —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),    —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),    —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),    —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),    —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),    —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a),    —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),    wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)    hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀    cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,    each of which is further optionally substituted with one, two,    three, or four, substituents Q^(a); or (iii) R^(b) and R^(c)    together with the N atom to which they are attached form    heterocyclyl, which is further optionally substituted with one, two,    three, or four, substituents Q^(a);-   wherein each Q^(a) is independently selected from the group    consisting of (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,    heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),    —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g),    —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g),    —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h),    —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),    —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),    —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),    —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),    R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅    aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g)    together with the N atom to which they are attached form    heterocyclyl;-   wherein two substituents Q that are adjacent to each other    optionally form a C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or    heterocyclyl, each optionally substituted with one, two, three, or    four substituents Q^(a); and-   (ii) an effective amount of a CD20 inhibitor to a patient in need    thereof.

In some embodiments, R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, orheteroaryl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —S(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1b),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).

In some embodiments, R^(5a) and R^(5b) are each independently (a) halo;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).

In some embodiments, R^(5a) and R^(5b) are each methyl, optionallysubstituted with one, two or three halos. In some embodiments, n is 1.In some embodiments, n is 1 and R^(5f) and R^(5g) are each hydrogen. Insome embodiments, n is 0. In some embodiments, m is 0.

In some embodiments, the compound of Formula (I) is of Formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

-   R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each    independently (a) hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅    aralkyl, heteroaryl, or heterocyclyl, each of which is optionally    substituted with one, two, three, or four substituents Q^(a); or (c)    —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),    —OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),    —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),    —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),    —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),    —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),    —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a),    —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), or —S(O)₂NR^(b)R^(c); or-   two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent    to each other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or    heterocyclyl, each optionally substituted with one, two, three, or    four substituents Q^(a).

In some embodiments, the compound of Formula (I) is Compound A35:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound A36:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound A68:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound A70:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound A37:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound A38:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound A41:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound A42:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound A43:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the compound of Formula (I) is Compound A44:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, the CD20 inhibitor is ofatumumab, obinutuzumab,rituximab, ocaratuzumab, ocrelizumab, tositumomab, ibritumomab tiuxetan,tisotumab vedotin, ublituximab, TRU-015, veltuzumab, BTCT4465A (RG7828),EDC9, MT-3724, or a variant or biosimilar thereof, or combinationsthereof.

In some embodiments, the disease being treated is cancer.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are pharmaceutical compositions comprising a PI3Kinhibitor and a CD20 inhibitor. In some instances, the pharmaceuticalcompositions described herein may be used for treating diseases ordisorders associated with excessive cell proliferation, such as cancer.Also described herein are methods of treating the proliferative diseasesand disorders with i) a PI3K inhibitor; and ii) a CD20 inhibitor.

Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well-known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs. The term“subject” refers to an animal, including, but not limited to, a primate(e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, ormouse. The terms “subject” and “patient” are used interchangeably hereinin reference, for example, to a mammalian subject, such as a humansubject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The terms “therapeutically effective amount” or “effective amount” aremeant to include the amount of a compound that, when administered, issufficient to prevent development of, or alleviate to some extent, oneor more of the symptoms of the disorder, disease, or condition beingtreated. The terms “therapeutically effective amount” or “effectiveamount” also refer to the amount of a compound that is sufficient toelicit the biological or medical response of a biological molecule(e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, orhuman, which is being sought by a researcher, veterinarian, medicaldoctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition, Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition, Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a disorder, disease,or condition. As used herein, “active ingredient” and “active substance”may be an optically active isomer of a compound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a disorder, disease, or condition.

The term “naturally occurring” or “native” when used in connection withbiological materials such as nucleic acid molecules, polypeptides, hostcells, and the like, refers to materials which are found in nature andare not manipulated by man. Similarly, “non-naturally occurring” or“non-native” refers to a material that is not found in nature or thathas been structurally modified or synthesized by man.

The term “PI3K” refers to a phosphoinositide 3-kinase or variantthereof, which is capable of phosphorylating the inositol ring of PI inthe D-3 position. The term “PI3K variant” is intended to includeproteins substantially homologous to a native PI3K, i.e., proteinshaving one or more naturally or non-naturally occurring amino aciddeletions, insertions, or substitutions (e.g., PI3K derivatives,homologs, and fragments), as compared to the amino acid sequence of anative PI3K. The amino acid sequence of a PI3K variant is at least about80% identical, at least about 90% identical, or at least about 95%identical to a native PI3K. Examples of PI3K include, but are notlimited to, p110α, p110β, p110δ, p110γ, PI3K-C2α, PI3K-C2β, PI3K-C2γ,Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res.1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PI3Ksare classified into at least four classes. Class I includes p110α,p110β, p110δ, and p110γ. Class II includes PI3K-C2α, PI3K-C2β, andPI3K-C2γ. Class III includes Vps34. Class IV includes mTOR, ATM, ATR,and DNA-PK. In certain embodiments, the PI3K is a Class I kinase. Incertain embodiments, the PI3K is p110α, p110γ, p110δ, or p110γ. Incertain embodiments, the PI3K is a variant of a Class I kinase. Incertain embodiments, the PI3K is a p110α mutant. Examples of p110αmutants include, but are not limited to, R38H, G106V, K111N, K227E,N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q,H710P, 1800L, T1025S, M10431, M1043V, H1047L, H1047R, and H1047Y(Ikenoue et al., Cancer Res. 2005, 65, 4562-4567; Gymnopoulos et al.,Proc. Natl. Acad Sci., 2007, 104, 5569-5574). In certain embodiments,the PI3K is a Class II kinase. In certain embodiments, the PI3K isPI3K-C2α, PI3K-C2β, or PI3K-C2γ. In certain embodiments, the PI3K is aClass III kinase. In certain embodiments, the PI3K is Vps34. In certainembodiments, the PI3K is a Class IV kinase. In certain embodiments, thePI3K is mTOR, ATM, ATR, or DNA-PK.

The term “CD20” refers to an activated-glycosylated phosphoproteinexpressed on the surface of all B-cells beginning at the pro-B phase(CD45R+, CD117+) and progressively increasing in concentration untilmaturity. The CD20 in humans is encoded by the MS4A1 gene. This geneencodes a member of the membrane-spanning 4A gene family. Members ofthis nascent protein family are characterized by common structuralfeatures and similar intron/exon splice boundaries and display uniqueexpression patterns among hematopoietic cells and nonlymphoid tissues.This gene encodes a B-lymphocyte surface molecule that plays a role inthe development and differentiation of B-cells into plasma cells. Thisfamily member is localized to 11q12, among a cluster of family members.Alternative splicing of this gene results in two transcript variantsthat encode the same protein. The protein has no known natural ligandand its function is to enable optimal B-cell immune response,specifically against T-independent antigens. It is suspected that itacts as a calcium channel in the cell membrane. It has been shown thatCD20 plays a role in the microenvironmental interactions of B cells andare therefore used to treat some types of cancer.

The term “antibody” refers to (a) immunoglobulin polypeptides andimmunologically active portions of immunoglobulin polypeptides, i.e.,polypeptides of the immunoglobulin family, or fragments thereof, thatcontain an antigen binding site that specifically binds to a specificantigen, or (b) conservatively substituted derivatives of suchimmunoglobulin polypeptides or fragments that specifically bind to theantigen. Examples of antibody fragments include, but are not limited to,a Fab, Fab′, F(ab′)2, Fd, Fv, scFv and scFv-Fc fragment, diabody,triabody, tetrabody, linear antibody, single-chain antibody, and othermultispecific antibodies formed from antibody fragments. (See Holligerand Hudson, 2005, Nat. Biotechnol. 23: 1126-1136.) The immunoglobulinmolecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY),class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass ofimmunoglobulin molecule. Included in the term immunoglobulin are thoseimmunoglobulin molecules that have modifications in the constant region,including modification (e.g., substitutions, deletions or additions) inamino acid residues that interact with Fey receptors. Antibodies aregenerally described in, for example, Harlow & Lane, Antibodies: ALaboratory Manual (Cold Spring Harbor Laboratory Press, 1988).

The term “monoclonal antibody” (mAb) refers to an antibody obtained froma population of substantially homogeneous antibodies; that is, theindividual antibodies comprising the population are identical except fornaturally occurring mutations that may be present in minor amounts.Monoclonal antibodies are highly specific, being directed against asingle antigenic determinant, also referred to as an epitope. Themodifier “monoclonal” is indicative of a substantially homogeneouspopulation of antibodies directed to the identical epitope and is not tobe construed as requiring production of the antibody by any particularmethod. Monoclonal antibodies can be made by any technique ormethodology known in the art; for example, the hybridoma method firstdescribed by Kohler et al., 1975, Nature 256:495, or recombinant DNAmethods known in the art (see, e.g., U.S. Pat. No. 4,816,567). Inanother example, monoclonal antibodies can also be isolated from phageantibody libraries, using techniques described in Clackson et al., 1991,Nature 352: 624-628, and Marks et al., 1991, J. Mol. Biol. 222:581-597.In contrast, the antibodies in a preparation of polyclonal antibodiesare typically a heterogeneous population of immunoglobulin isotypesand/or classes and also exhibit a variety of epitope specificity.

The term “biosimilar” or “follow-on biologic” or “subsequent entrybiologic” refers to a biologic medical product which is almost anidentical copy of an original product that is manufactured by adifferent company. Biosimilars are officially approved versions oforiginal “innovator” products, and can be manufactured when the originalproduct's patent expires. Reference to the innovator product is anintegral component of the approval. A biosimilar biological product ishighly similar to the reference product notwithstanding minordifferences in clinically inactive components, and there are noclinically meaningful differences between the biological product and thereference product in terms of the safety, purity, and potency of theproduct.

The term “variant” when referring to an antibody as disclosed herein caninclude any antibody that retains at least some of the activity, e.g.,antigen-binding activity, of the reference antibody, but which isstructurally different. Variants include fragments of antibodies (e.g.,Fab, Fab′ and F(ab′)2, Fd, Fvs, single-chain Fvs (scFv), single-chainantibodies, disulfide-linked Fvs (sdFv) fragments) and also antibodieswith altered amino acid sequences, e.g., in the variable domains, due toamino acid substitutions, deletions, or insertions. Variants can occurspontaneously or be intentionally constructed. Intentionally constructedvariants can be produced using art-known mutagenesis techniques. Variantantibodies can comprise conservative or non-conservative amino acidsubstitutions, deletions or additions. The variations are limited by theconstraint that the antibody maintains a function of the referenceantibody, e.g., binding to the same epitope as the reference antibody,or competitively inhibiting the reference antibody.

The terms “synergy,” “synergism,” or “synergistic” as used herein referto a combination of therapies (e.g., use of a PI3K inhibitor of Formula(I) and an anti-CD20 antibody) that is more effective than the expectedadditive effects of any two or more single therapies. For example, asynergistic effect of a combination of therapies permits the use oflower dosages of one or more of the therapies and/or less frequentadministration of said therapies to a subject. The ability to utilizelower dosages of therapies and/or to administer the therapies lessfrequently reduces the toxicity associated with the administration ofthe therapies to a subject without reducing the efficacy of saidtherapies in the prevention, management, treatment, or amelioration of agiven disease, such as a B cell malignancy. In addition, a synergisticeffect can result in improved efficacy of therapies in the prevention,management, treatment, or amelioration of a given disease, such as a Bcell malignancy. Finally, synergistic effects of a combination oftherapies may avoid or reduce adverse or unwanted side effectsassociated with the use of any single therapy. The “synergy,”“synergism,” or “synergistic” effect of a combination may be determinedherein by the methods of Chou et al., and/or Clarke et al. See Ting-ChaoChou, Theoretical Basis, Experimental Design, and ComputerizedSimulation of Synergism and Antagonism in Drug Combination Studies,Pharmacol Rev 58:621-681 (2006), and Clarke et al., Issues inexperimental design and endpoint analysis in the study of experimentalcytotoxic agents in vivo in breast cancer and other models, BreastCancer Research and Treatment 46:255-278 (1997), which are bothincorporated by reference for the methods of determining the “synergy,”synergism,” or “synergistic” effect of a combination.

The term “isotopic variant” refers to a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such a compound. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),tritium (³H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C),carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15(¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17(¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F),phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32(³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36(³⁶S), chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl),bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I), iodine-125(¹²⁵I), iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). Incertain embodiments, an “isotopic variant” of a compound is in a stableform, that is, non-radioactive. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),carbon-12 (¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N),oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F),phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an “isotopic variant” of a compound is in an unstable form,that is, radioactive. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, for example, or any carboncan be ¹³C, for example, or any nitrogen can be ¹⁵N, for example, or anyoxygen can be ¹⁸O, for example, where feasible according to the judgmentof one of skill. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of deuterium (D).

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkylene may optionally be substitutedwith one or more substituents Q as described herein. The term “alkyl”also encompasses both linear and branched alkyl, unless otherwisespecified. In certain embodiments, the alkyl is a linear saturatedmonovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃₋₆ alkyl groups are also referred as “loweralkyl.” Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl (including all isomeric forms), n-propyl,isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl(including all isomeric forms). For example, C₁₋₆ alkyl refers to alinear saturated monovalent hydrocarbon radical of 1 to 6 carbon atomsor a branched saturated monovalent hydrocarbon radical of 3 to 6 carbonatoms.

The term “alkylene” refers to a linear or branched saturated divalenthydrocarbon radical, wherein the alkylene may optionally be substitutedwith one or more substituents Q as described herein. The term “alkylene”encompasses both linear and branched alkylene, unless otherwisespecified. In certain embodiments, the alkylene is a linear saturateddivalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅),1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branched saturateddivalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆and branched C₃₋₆ alkylene groups are also referred as “lower alkylene.”Examples of alkylene groups include, but are not limited to, methylene,ethylene, propylene (including all isomeric forms), n-propylene,isopropylene, butylene (including all isomeric forms), n-butylene,isobutylene, t-butylene, pentylene (including all isomeric forms), andhexylene (including all isomeric forms). For example, C₁₋₆ alkylenerefers to a linear saturated divalent hydrocarbon radical of 1 to 6carbon atoms or a branched saturated divalent hydrocarbon radical of 3to 6 carbon atoms.

The term “heteroalkylene” refers to a linear or branched saturateddivalent hydrocarbon radical that contains one or more heteroatoms eachindependently selected from O, S, and N in the hydrocarbon chain. Forexample, C₁₋₆ heteroalkylene refers to a linear saturated divalenthydrocarbon radical of 1 to 6 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the heteroalkylene is a linear saturated divalenthydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10(C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branched saturated divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ heteroalkylene groups are also referred as “lowerheteroalkylene.” Examples of heteroalkylene groups include, but are notlimited to, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —CH₂NH—, —CH₂NHCH₂—,—CH₂CH₂NH—, —CH₂S—, —CH₂SCH₂—, and —CH₂CH₂S—. In certain embodiments,heteroalkylene may also be optionally substituted with one or moresubstituents Q as described herein.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one, two, three,four, or five, in another embodiment, one, carbon-carbon double bond(s).The alkenyl may be optionally substituted with one or more substituentsQ as described herein. The term “alkenyl” also embraces radicals having“cis” and “trans” configurations, or alternatively, “Z” and “E”configurations, as appreciated by those of ordinary skill in the art. Asused herein, the term “alkenyl” encompasses both linear and branchedalkenyl, unless otherwise specified. For example, C₂₋₆ alkenyl refers toa linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbonatoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propen-1-yl, propen-2-yl,allyl, butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, one,two, three, four, or five, in another embodiment, one, carbon-carbondouble bond(s). The alkenylene may be optionally substituted with one ormore substituents Q as described herein. Similarly, the term“alkenylene” also embraces radicals having “cis” and “trans”configurations, or alternatively, “E” and “Z” configurations. As usedherein, the term “alkenylene” encompasses both linear and branchedalkenylene, unless otherwise specified. For example, C₂₋₆ alkenylenerefers to a linear unsaturated divalent hydrocarbon radical of 2 to 6carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3to 6 carbon atoms. In certain embodiments, the alkenylene is a lineardivalent hydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenylene groupsinclude, but are not limited to, ethenylene, allylene, propenylene,butenylene, and 4-methylbutenylene.

The term “heteroalkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, one,two, three, four, or five, in another embodiment, one, carbon-carbondouble bond(s), and which contains one or more heteroatoms eachindependently selected from O, S, and N in the hydrocarbon chain. Theheteroalkenylene may be optionally substituted with one or moresubstituents Q as described herein. The term “heteroalkenylene” embracesradicals having a “cis” or “trans” configuration or a mixture thereof,or alternatively, a “Z” or “E” configuration or a mixture thereof, asappreciated by those of ordinary skill in the art. For example, C₂₋₆heteroalkenylene refers to a linear unsaturated divalent hydrocarbonradical of 2 to 6 carbon atoms or a branched unsaturated divalenthydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, theheteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20(C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched divalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examplesof heteroalkenylene groups include, but are not limited to, —CH═CHO—,—CH═CHOCH₂—, —CH═CHCH₂O—, —CH═CHS—, —CH═CHSCH₂—, —CH═CHCH₂S—, or—CH═CHCH₂NH—.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one, two, three,four, or five, in another embodiment, one, carbon-carbon triple bond(s).The alkynyl may be optionally substituted with one or more substituentsQ as described herein. The term “alkynyl” also encompasses both linearand branched alkynyl, unless otherwise specified. In certainembodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀),3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms.Examples of alkynyl groups include, but are not limited to, ethynyl(—C≡CH) and propargyl (—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to alinear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atomsor a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms.

The term “cycloalkyl” refers to a cyclic saturated bridged and/ornon-bridged monovalent hydrocarbon radical, which may be optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, the cycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

The term “cycloalkenyl” refers to a cyclic unsaturated, nonaromaticbridged and/or non-bridged monovalent hydrocarbon radical, which may beoptionally substituted with one or more substituents Q as describedherein. In certain embodiments, the cycloalkenyl has from 3 to 20(C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), or from 3 to 7(C₃₋₇) carbon atoms. Examples of cycloalkyl groups include, but are notlimited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl,

The term “aryl” refers to a monocyclic aromatic group and/or multicyclicmonovalent aromatic group that contain at least one aromatic hydrocarbonring. In certain embodiments, the aryl has from 6 to 20 (C₆₋₂₀), from 6to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples of arylgroups include, but are not limited to, phenyl, naphthyl, fluorenyl,azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Arylalso refers to bicyclic or tricyclic carbon rings, where one of therings is aromatic and the others of which may be saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments,aryl may be optionally substituted with one or more substituents Q asdescribed herein.

The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl groupsubstituted with one or more aryl groups. In certain embodiments, thearalkyl has from 7 to 30 (C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7 to 16(C₇₋₁₆) carbon atoms. Examples of aralkyl groups include, but are notlimited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certainembodiments, the aralkyl are optionally substituted with one or moresubstituents Q as described herein.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupor monovalent polycyclic aromatic group that contain at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, N, and P in the ring. Aheteroaryl group is bonded to the rest of a molecule through itsaromatic ring. Each ring of a heteroaryl group can contain one or two 0atoms, one or two S atoms, one to four N atoms, and/or one or two Patoms, provided that the total number of heteroatoms in each ring isfour or less and each ring contains at least one carbon atom. In certainembodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to10 ring atoms. Examples of monocyclic heteroaryl groups include, but arenot limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl,tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroarylgroups include, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, theheteroaryl may also be optionally substituted with one or moresubstituents Q as described herein as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system or monovalent polycyclic ring systemthat contains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, N, and P; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. A heterocyclyl group is bonded to the rest of a moleculethrough its non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay be spiro, fused, or bridged, and in which nitrogen or sulfur atomsmay be optionally oxidized, nitrogen atoms may be optionallyquaternized, and some rings may be partially or fully saturated, oraromatic. The heterocyclyl may be attached to the main structure at anyheteroatom or carbon atom which results in the creation of a stablecompound. Examples of such heterocyclic groups include, but are notlimited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl,benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl may alsobe optionally substituted with one or more substituents Q as describedherein.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkylene, heteroalkylene, alkenyl,alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkenyl, aryl,aralkyl, heteroaryl, heteroaryl-C₁₋₆ alkyl, and heterocyclyl group, maybe substituted with one or more substituents Q, each of which isindependently selected from, e.g., (a) oxo (═O), halo, cyano (—CN), andnitro (—NO₂); (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl,each of which is further optionally substituted with one or more, in oneembodiment, one, two, three, four, or five, substituents Q^(a); and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR ^(b)R^(c),—OS(O)₂NR ^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a). As usedherein, all groups that can be substituted are “optionally substituted,”unless otherwise specified.

In one embodiment, each substituent Q^(a) is independently selected fromthe group consisting of (a) oxo, cyano, halo, and nitro; and (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —P(O)(OR^(g)R^(h),—P(O)(OR^(e))R^(h), —P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (ii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or moreof the desired enantiomer and about 5% or less of the less preferredenantiomer based on the total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The phrase “an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof”has the same meaning as the phrase “an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, or an isotopicvariant of the compound referenced therein; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug of the compound referencedtherein; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug of an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, or an isotopic variant of the compound referencedtherein.”

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in a stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

The terms “resistent,” “relapsed,” or “refractory” refer to a cancerthat has a reduced responsiveness to a treatment, e.g., the point atwhich the cancer does not respond to attempted forms of treatment. Thecancer can be resistant at the beginning of treatment or it may becomeresistant during treatment. The term “refractory” can refer to a cancerfor which treatment (e.g., chemotherapy drugs, biological agents, and/orradiation therapy) has proven to be ineffective. A refractory cancertumor may shrink, but not to the point where the treatment is determinedto be effective. Typically however, the tumor stays the same size as itwas before treatment (stable disease), or it grows (progressivedisease).

“Responsiveness” or to “respond” to treatment, and other forms of thisterm, as used herein, refer to the reaction of a subject to treatmentwith a therapeutic, e.g., a PI3K inhibitor, alone or in combination,e.g., monotherapy or combination therapy. Responsiveness to a therapy,e.g., treatment with a PI3K inhibitor alone or in combination, can beevaluated by comparing a subject's response to the therapy using one ormore clinical criteria, such as IWCLL 2008 (for CLL) described in, e.g.,Hallek, M. et al. (2008) Blood 111 (12): 5446-5456; the LuganoClassification described in, e.g., Cheson, B. D. et al. Journal ofClinical Oncology, 32(27): 3059-3067; and the like. Additionalclassifications of responsiveness are provided by. These criteriaprovide a set of published rules that define when cancer patientsimprove (“respond”), stay the same (“stable”) or worsen (“progression”)during treatments.

For example, a subject having CLL can be determined to be in completeremission (CR) or partial remission (PR). For example, according toIWCLL 2008, a subject is considered to be in CR if at least all of thefollowing criteria as assessed after completion of therapy are met: (i)Peripheral blood lymphocytes (evaluated by blood and different count)below 4×10⁹/L (4000 μi.); (ii) no hepatomegaly or splenomegaly byphysical examination; (iii) absence of constitutional symptoms; and (iv)blood counts (e.g., neutrophils, platelets, hemoglobin) above the valuesset forth in Hallek, M. et al. Partial remission (PR) for CLL is definedaccording to IWCLL 2008 as including one of: (i) a decrease in number ofblood lymphocytes by 50% or more from the value before therapy; (ii) areduction in lymphadenopathy, as detected by CT scan or palpation; or(iii) a reduction in pretreatment enlargement of spleen or liver by 50%or more, as detected by CT scan or palpation; and blood counts (e.g.,neutrophils, platelets, hemoglobin) according to the values set forth inHallek, M. et al. In other embodiments, a subject having CLL isdetermined to have progressive disease (PD) or stable disease (SD). Forexample, according to IWCLL 2008, a subject is considered to be in PDduring therapy or after therapy if at least one of the followingcriteria is met: (i) progression on lymphadenopathy; (ii) an increase inpretreatment enlargement of spleen or liver by 50% or more, or de novoappearance of hepatomegaly or splenomegaly; (iii) an increase in thenumber of blood lymphocytes by 50% or more with at least 5000 Blymphocytes per microliter; (iv) transformation to a more aggressivehistology (e.g., Richter syndrome); or (v) occurrence of cytopenia(neutropenia, anemia or thrombocytopenia) attributable to CLL. Stabledisease (SD) for CLL is defined according to IWCLL 2008 as a patient whohas not achieved CR or a PR, and who has not exhibited progressivedisease.

For example, in some embodiments, a subject with CLL responds totreatment with a PI3K inhibitor, alone or in combination, if at leastone of the criteria for disease progression according to IWCLL isretarded or reduced, e.g., by about 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90% or more. In another example, a subject responds to treatmentwith a PI3K inhibitor, alone or in combination, if the subjectexperiences a life expectancy extension, e.g., extended by about 5%,10%, 20%, 30%, 40%, 50% or more beyond the life expectancy predicted ifno treatment is administered. In another example, a subject responds totreatment with a PI3K inhibitor, alone or in combination, if the subjecthas one or more of: an increased progression-free survival, overallsurvival or increased time to progression (TTP), e.g., as described inHallek, M. et al.

Compounds

Disclosed herein are PI3K inhibitors of Formula (I):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

-   X, Y, and Z are each independently N or CR^(X), with the proviso    that at least two of X, Y, and Z are nitrogen atoms; where R^(X) is    hydrogen or C₁₋₆ alkyl;-   R¹ and R² are each independently (a) hydrogen, cyano, halo, or    nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,    C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a),    R^(1b), R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,    C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(1b) and    R^(1c) together with the N atom to which they are attached form    heterocyclyl;-   R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and    R⁴ are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆    heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;-   R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —C(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or    —(CR^(5f)R^(5g))_(n)-heteroaryl;-   R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one    occurrence of R^(5f) and one occurrence of R^(5g) are attached to    the same carbon atom, the R^(5f) and R^(5g) together with the carbon    atom to which they are attached form a C₃₋₁₀ cycloalkyl or    heterocyclyl;-   R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or    —SO₂—C₁₋₆ alkyl;-   m is 0 or 1; and-   n is 0, 1, 2, 3, or 4;-   wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,    heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl,    and heterocyclyl in R¹, R², R³, R⁴, R⁶, R^(X), R^(1a), R^(1b),    R^(1c), R^(1d), R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f) and    R^(5g) is optionally substituted with one or more, in one    embodiment, one, two, three, four, or five substituents Q, wherein    each substituent Q is independently selected from (a) oxo, cyano,    halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀    cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl,    each of which is further optionally substituted with one or more, in    one embodiment, one, two, three, or four, substituents Q^(a);    and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),    —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),    —OC(O)NleR^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),    —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),    —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),    —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),    —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a),    —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),    wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)    hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀    cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,    each of which is further optionally substituted with one or more, in    one embodiment, one, two, three, or four, substituents Q^(a);    or (iii) R^(b) and R^(c) together with the N atom to which they are    attached form heterocyclyl, which is further optionally substituted    with one or more, in one embodiment, one, two, three, or four,    substituents Q^(a);-   wherein each Q^(a) is independently selected from the group    consisting of (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,    heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),    —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g),    —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g),    —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h),    —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),    —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),    —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),    —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),    R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅    aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g)    together with the N atom to which they are attached form    heterocyclyl; or-   wherein two substituents Q that are adjacent to each other    optionally form a C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or    heterocyclyl, each optionally substituted with one, two, three, or    four substituents Q^(a).-   In one embodiment of a compound of Formula (I),-   X, Y, and Z are each independently N or CR^(X), with the proviso    that at least two of X, Y, and Z are nitrogen atoms; where R^(x) is    hydrogen or C₁₋₆ alkyl;-   R¹ and R² are each independently (a) hydrogen, cyano, halo, or    nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,    C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a),    R^(1b), R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,    C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(1b) and    R^(1c) together with the N atom to which they are attached form    heterocyclyl;-   R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and    R⁴ are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆    heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;-   R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR¹⁰R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or    —(CR^(5f)R^(5g))_(n)-heteroaryl;-   R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one    occurrence of R^(5f) and one occurrence of R^(5g) are attached to    the same carbon atom, the R^(5f) and R^(5g) together with the carbon    atom to which they are attached form a C₃₋₁₀ cycloalkyl or    heterocyclyl;-   R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or    —SO₂—C₁₋₆ alkyl;-   m is 0 or 1; and-   n is 0, 1, 2, 3, or 4;-   wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,    heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl,    and heterocyclyl is optionally substituted with one or more, in one    embodiment, one, two, three, four, or five substituents Q as defined    herein.

In another embodiment of a compound of Formula (I),

-   X, Y, and Z are each independently N or CR^(X), with the proviso    that at least two of X, Y, and Z are nitrogen atoms; where R^(X) is    hydrogen or C₁₋₆ alkyl;-   R¹ and R² are each independently (a) hydrogen, cyano, halo, or    nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,    C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a),    R^(1b), R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,    C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(1b) and    R^(1c) together with the N atom to which they are attached form    heterocyclyl;-   R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and    R⁴ are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆    heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene; R^(5a)    is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(C)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(C)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(C)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or    —(CR^(5f)R^(5g))_(n)-heteroaryl;-   R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(C)NR^(1b)R^(1c),    —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),    —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(C)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(C)NR^(1b)R^(1c),    —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),    —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(C)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one    occurrence of R^(5f) and one occurrence of R^(5g) are attached to    the same carbon atom, the R^(5f) and R^(5g) together with the carbon    atom to which they are attached form a C₃₋₁₀ cycloalkyl or    heterocyclyl;-   R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or    —SO₂—C₁₋₆ alkyl;-   m is 0 or 1; and-   n is 0, 1, 2, 3, or 4;-   wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,    heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl,    and heterocyclyl is optionally substituted with one or more, in one    embodiment, one, two, three, four, or five substituents Q as defined    herein.

In yet another embodiment of a compound of Formula (I),

-   X, Y, and Z are each independently N or CR^(X), with the proviso    that at least two of X, Y, and Z are nitrogen atoms; where R^(X) is    hydrogen or C₁₋₆ alkyl;-   R¹ and R² are each independently (a) hydrogen, cyano, halo, or    nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,    C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a),    R^(1b), R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,    C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(1b) and    R^(1c) together with the N atom to which they are attached form    heterocyclyl;-   R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and    R⁴ are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆    heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;-   R^(5a) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(C)NR^(1b)R^(1c), —NR^(1a)C(═NR¹)NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(C)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(C)NR^(1b)R^(1c), —NR^(1a)C(═NR¹)NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(C)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R⁵ is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or    —(CR^(5f)R^(5g))_(n)-heteroaryl;-   R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one    occurrence of R^(5f) and one occurrence of R^(5g) are attached to    the same carbon atom, the R^(5f) and R^(5g) together with the carbon    atom to which they are attached form a C₃₋₁₀ cycloalkyl or    heterocyclyl;-   R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or    —SO₂—C₁₋₆ alkyl;-   m is 0 or 1; and-   n is 0, 1, 2, 3, or 4;-   wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,    heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl,    and heterocyclyl is optionally substituted with one or more, in one    embodiment, one, two, three, four, or five substituents Q as defined    herein.

In still another embodiment of a compound of Formula (I),

-   X, Y, and Z are N;-   R¹ and R² are each independently (a) hydrogen, cyano, halo, or    nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,    C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a),    R^(1b), R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,    C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(1b) and    R^(1c) together with the N atom to which they are attached form    heterocyclyl;-   R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and    R⁴ are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆    heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;-   R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or    heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR¹)NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, or heteroaryl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or    —(CR^(5f)R^(5g))_(n)-heteroaryl;-   R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);-   R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b)    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄    aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)    —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),    —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a), —OC(O)OR^(1a),    —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),    —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),    —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),    —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),    —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),    —NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),    —S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one    occurrence of R^(5f) and one occurrence of R^(5g) are attached to    the same carbon atom, the R^(5f) and R^(5g) together with the carbon    atom to which they are attached form a C₃₋₁₀ cycloalkyl or    heterocyclyl;-   R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or    —SO₂—C₁₋₆ alkyl;-   m is 0 or 1; and-   n is 0, 1, 2, 3, or 4;-   wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,    heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl,    and heterocyclyl is optionally substituted with one or more, in one    embodiment, one, two, three, four, or five substituents Q as defined    herein.

In some embodiments of compounds of structural Formula (I):

X, Y, and Z are each N;

R¹ and R² are each hydrogen;

R³ and R⁴ are each hydrogen;

Rya is C₁₋₆ alkyl;

R^(5b) is C₁₋₆ alkyl;

R^(5c) is —(CH₂)-phenyl, wherein R^(5c) is optionally substituted withone, two, three, or four, substituents Q;

R^(5d) and R^(5e) are each hydrogen;

R⁶ is CHF₂; and

m is 0;

wherein each alkyl is optionally substituted with one, two, three, orfour, substituents Q, wherein each substituent Q is independentlyselected from C₆₋₁₄ aryl, heteroaryl, and heterocyclyl, each of which isfurther optionally substituted with one, two, three, or four,substituents Q^(a), wherein the heteroaryl has from 5 to 10 ring atomsand one or more heteroatoms independently selected from O, S, and N, andthe heterocyclyl has from 3 to 15 ring atoms and one or more heteroatomsindependently selected from O, S, and N;

wherein each Q^(a) is independently selected from the group consistingof halo, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl and —OR^(e), wherein R^(e) ishydrogen or C₁₋₆ alkyl.

Also provided herein is a compound of Formula (IX):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic

variant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof; wherein: R^(7a), R^(7b), R^(7c), R^(7d),and R^(7e) are each in dependently (a) hydrogen, cyano, halo, or nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);or (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(e), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(e),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(e), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(e), —NR^(a)C(═NR^(d))NR^(b)R^(e), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(e), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), or—S(O)₂NR^(b)R^(c); or two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e)that are adjacent to each other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(1a),R^(1b), R^(1c), R^(1d), R^(5a), R^(5b), R^(5d), R^(5e), X, Y, and Z areeach as defined herein.

In certain embodiments of compounds of Formula (IX), one of R^(7a),R^(7b), R^(7e), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, one ofR^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, e.g., phenyl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is heteroaryl, e.g., 5-membered or 6-membered heteroaryl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formula (IX), R^(7a) is C₆₋₁₄aryl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, R^(7a) is C₆₋₁₄ aryl, e.g., phenyl, optionally substitutedwith one, two, three, or four substituents Q^(a); in certainembodiments, R^(7a) is heteroaryl, e.g., 5-membered or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is heterocyclyl,e.g., 5-membered or 6-membered heterocyclyl, optionally substituted withone, two, three, or four substituents Q^(a); in certain embodiments,R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formula (IX),

-   R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionally    substituted with one, two, three, four, or five substituents Q;-   R² is hydrogen;-   R³ and R⁴ are hydrogen;-   R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four,    or five substituents Q;-   R^(5a) and R^(5b) are each independently hydrogen, halo, C₁₋₆ alkyl,    optionally substituted with one, two, three, four, or five    substituents Q;-   R^(5d) and R^(5e) are each independently C₁₋₆ alkyl, optionally    substituted with one, two, three, four, or five substituents Q;-   R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which is    optionally substituted with one, two, three, or four substituents    Q^(a);-   R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and-   X, Y, and Z are each independently N or CR^(x), with the proviso    that at least two of X, Y, and Z are N;-   where R^(x) is a hydrogen or C₁₋₆ alkyl, optionally substituted with    one, two, three, or four substituents Q^(a).

In certain embodiments of compounds of Formula (IX),

-   R¹ is hydrogen or methoxy;-   R² is hydrogen;-   R³ and R⁴ are hydrogen;-   R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;-   R^(5a) and R^(5b) are hydrogen;-   R^(5d) and R^(5e) are each independently C₁₋₆ alkyl;-   R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which is    optionally substituted with one, two, three, or four substituents    Q^(a);-   R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and-   X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formula (IX),

-   R¹ is hydrogen or methoxy;-   R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formula (IX),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formula (IX),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a);

R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formula (IX),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

Also provided herein is a compound of Formula (X):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(5d), R^(5c), R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) are each as defined herein.

In certain embodiments of compounds of Formula (X), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, one ofR^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, e.g., phenyl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is heteroaryl, e.g., 5-membered or 6-membered heteroaryl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formula (X), R^(7a) is C₆₋₁₄aryl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, R^(7a) is C₆₋₁₄ aryl, e.g., phenyl, optionally substitutedwith one, two, three, or four substituents Q^(a); in certainembodiments, R^(7a) is heteroaryl, e.g., 5-membered or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is heterocyclyl,e.g., 5-membered or 6-membered heterocyclyl, optionally substituted withone, two, three, or four substituents Q^(a); in certain embodiments,R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formula (X),

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently hydrogen, halo, C₁₋₆ alkyl,optionally substituted with one, two, three, four, or five substituentsQ;

R^(5d) and R^(5e) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In certain embodiments of compounds of Formula (X),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5b) are each independently C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In certain embodiments of compounds of Formula (X),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In certain embodiments of compounds of Formula (X),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In certain embodiments of compounds of Formula (X),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5b) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In certain embodiments of compounds of Formula (X),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

Provide herein is a compound of Formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

-   R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each    independently (a) hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅    aralkyl, heteroaryl, or heterocyclyl, each of which is optionally    substituted with one, two, three, or four substituents Q^(a); or (c)    —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),    —OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),    —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),    —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),    —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),    —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),    —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a),    —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), or —S(O)₂NR^(b)R^(c); or    two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent    to each other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or    heterocyclyl, each optionally substituted with one, two, three, or    four substituents Q^(a); and-   R¹, R², R³, R⁴, R⁶, R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b),    R^(5f), R^(5g), X, Y, and Z are each as defined herein.

In certain embodiments of compounds of Formula (XI), R^(5a) and R^(5b)are each independently (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R^(5f),R^(5g), R⁶, R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, Z, R^(1a),R_(1b), R_(1c), and R^(1d) are defined herein elsewhere.

In certain embodiments of compounds of Formula (XI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, one ofR^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, e.g., phenyl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is heteroaryl, e.g., 5-membered or 6-membered heteroaryl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a);in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formula (XI), R^(7a) is C₆₋₁₄aryl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a); in certainembodiments, R^(7a) is C₆₋₁₄ aryl, e.g., phenyl, optionally substitutedwith one, two, three, or four substituents Q^(a); in certainembodiments, R^(7a) is heteroaryl, e.g., 5-membered or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is heterocyclyl,e.g., 5-membered or 6-membered heterocyclyl, optionally substituted withone, two, three, or four substituents Q^(a); in certain embodiments,R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q^(a); in certain embodiments, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); in certain embodiments, R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments of compounds of Formula (XI),

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R^(5f) and R^(5g) are each independently hydrogen, halo, C₁₋₆ alkyl,optionally substituted with one, two, three, four, or five substituentsQ; or R^(5f) and R^(5g) together with the carbon atom to which they areattached form C₁₋₁₀ cycloalkyl or heterocyclyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(x) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one, two, three, or four substituents Q^(a).

In certain embodiments of compounds of Formula (XI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently C₁₋₆ alkyl;

R^(5f) and R^(5g) are each independently hydrogen or C₁₋₆ alkyl; orR^(5f) and R^(5g) together with the carbon atom to which they areattached form C₁₋₁₀ cycloalkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formula (XI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a);

R⁷⁰, R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formula (XI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formula (XI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In certain embodiments of compounds of Formula (XI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a);

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

Provided herein is a compound of Formula (XVI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), and R^(7e) are eachas defined herein.

In one embodiment of a compound of Formula (XVI), one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a), and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heteroaryl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7c), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is 5-membered or 6-memberedheteroaryl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heterocyclyl, which is optionallysubstituted with one, two, three, or four substituents Q^(a); and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is 5-membered or 6-memberedheterocyclyl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, piperidinyl, or piperazinyl, each optionally substituted withone, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a);and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment of a compound of Formula (XVI), one ofR^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl,3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVI), R^(7a) is C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are eachas defined herein.

In another embodiment of a compound of Formula (XVI), R^(7a) is C₆₋₁₄aryl, which is optionally substituted with one, two, three, or foursubstituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7c),R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isheteroaryl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) is5-membered or 6-membered heteroaryl, which is optionally substitutedwith one, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are eachas defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isheterocyclyl, which is optionally substituted with one, two, three, orfour substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) is5-membered or 6-membered heterocyclyl, which is optionally substitutedwith one, two, three, or four substituents Q^(a); and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are eachas defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isphenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl,each optionally substituted with one, two, three, or four substituentsQ^(a); and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d),R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isphenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q^(a); and R¹, R², R³, R⁴, R⁶, R^(5a),R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as definedherein.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In yet another embodiment of a compound of Formula (XVI), R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four, orfive substituents Q;

R^(5a) and R^(5b) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently C₁₋₆ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, or four substituents Q^(a);and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one, two, three, or foursubstituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one, two, three, four, or five substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI),

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, or four substituents Q^(a); and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment of a compound of Formula (XVI), R^(5a) and R^(5b) areeach independently (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R⁶,R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(1a), R^(1b), R^(1c), andR^(1d) are defined herein elsewhere.

In one embodiment of any of the formulae provided herein,

-   R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionally    substituted with one, two, three, four, or five substituents Q;-   R² is hydrogen;-   R³ and R⁴ are hydrogen;-   R⁶ is C₁₋₆ alkyl, optionally substituted with one, two, three, four,    or five substituents Q;-   R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl    optionally substituted with one, two, three, four, or five    substituents Q;-   R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which is    optionally substituted with one, two, three, or four substituents    Q^(a);-   R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and-   X, Y, and Z are each independently N or CR^(x), with the proviso    that at least two of X, Y, and Z are N;-   where R^(x) is a hydrogen or C₁₋₆ alkyl, optionally substituted with    one, two, three, or four substituents Q^(a).

In one embodiment of any of the formulae provided herein,

-   R¹ is hydrogen or methoxy;-   R² is hydrogen;-   R³ and R⁴ are hydrogen;-   R⁶ is C₁₋₆ alkyl, optionally substituted with one or more halo;-   R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;-   R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which is    optionally substituted with one, two, three, or four substituents    Q^(a);-   R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and-   X, Y, and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein,

-   R¹ is hydrogen or methoxy;-   R² is hydrogen;-   R³ and R⁴ are hydrogen;-   R⁶ is difluoromethyl;-   R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;-   R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic    heterocyclyl, each of which is optionally substituted with one, two,    three, or four substituents Q^(a);-   R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and-   X, Y, and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein,

-   R¹ is hydrogen or methoxy;-   R² is hydrogen;-   R³ and R⁴ are hydrogen;-   R⁶ is difluoromethyl;-   R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;-   R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered    heterocyclyl, each of which is optionally substituted with one, two,    three, or four substituents Q^(a);-   R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and-   X, Y, and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein,

-   R¹ is hydrogen or methoxy;-   R² is hydrogen;-   R³ and R⁴ are hydrogen;-   R⁶ is difluoromethyl;-   R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;-   R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,    pyrrolidinyl, piperidinyl, or piperazinyl, each of which is    optionally substituted with one, two, three, or four substituents    Q^(a);-   R^(7b), R^(7d), and R^(7e) are hydrogen; and-   X, Y, and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein,

-   R¹ is hydrogen or methoxy;-   R² is hydrogen;-   R³ and R⁴ are hydrogen;-   R⁶ is difluoromethyl;-   R^(5a) and R^(5b) are each independently hydrogen or C₁₋₆ alkyl;-   R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or    piperazinyl, each of which is optionally substituted with one, two,    three, or four substituents Q^(a);-   R^(7b), R^(7d), and R^(7e) are hydrogen; and-   X, Y, and Z are each independently N or CH.

The groups or variables, R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(5c),R^(5d), R^(5e), R^(5f), R^(5g), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e),m, n, X, Y, and Z in Formulae provided herein, e.g., Formulae (I), (IX),(X), (XI), (XVI), are further defined in the embodiments describedherein. All combinations of the embodiments provided herein for suchgroups and/or variables are within the scope of this disclosure.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ iscyano. In certain embodiments, R¹ is halo. In certain embodiments, R¹ isfluoro, chloro, bromo, or iodo. In certain embodiments, R¹ is nitro. Incertain embodiments, R¹ is C₁₋₆ alkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₂₋₆ alkenyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₂₋₆ alkynyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₃₋₁₀ cycloalkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₆₋₁₄ aryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is C₇₋₁₅ aralkyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is heteroaryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R¹ is heterocyclyl, optionally substituted with one, two,three, four, or five substituents Q as described herein.

In certain embodiments, R¹ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R¹ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R¹ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹ is —O—C₁₋₆ alkyl, wherein the alkyl is optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R¹ is methoxy, ethoxy, propoxy, isopropoxy, or3-dimethylaminopropoxy. In certain embodiments, R¹ is —OC(O)R^(1d),wherein R^(1a) is as defined herein. In certain embodiments, R¹ is—OC(O)OR^(1d), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹ is —OS(O)R^(1d), whereinR^(1d) is as defined herein. In certain embodiments, R¹ is—OS(O)₂R^(1d), wherein R^(1d) is as defined herein. In certainembodiments, R¹ is —OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R¹ is —NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R¹ is—NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R¹ is —NR^(1d)C(O)OR^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R¹is —NR^(1a)dC(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R¹ is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R¹ is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R¹is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹ is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R¹ is —S(O)R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R¹ is—S(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R² is hydrogen. In certain embodiments, R² iscyano. In certain embodiments, R² is halo. In certain embodiments, R² isfluoro, chloro, bromo, or iodo. In certain embodiments, R² is nitro. Incertain embodiments, R² is C₁₋₆ alkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R² is C₂₋₆ alkenyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is C₂₋₆ alkynyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is C₃₋₁₀ cycloalkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R² is C₃₋₇ cycloalkyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R² is C₆₋₁₄ aryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is C₇₋₁₅ aralkyl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is heteroaryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R² is heterocyclyl, optionally substituted with one, two,three, four, or five substituents Q as described herein.

In certain embodiments, R² is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R² is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R² is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R² is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R² is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹ is —O—C₁₋₆ alkyl, wherein the alkyl is optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R¹ is methoxy, ethoxy, propoxy, isopropoxy, or3-dimethylaminopropoxy. In certain embodiments, R² is —OC(O)R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R² is—OC(O)OR^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R² is —OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R² is—OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R² is —OS(O)R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R² is—OS(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R² is —OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R² is—OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R² is —NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R² is amino(—NH₂). In certain embodiments, R² is —NR^(1a)C(O)R^(1d), wherein R^(1a)and R^(1d) are each as defined herein. In certain embodiments, R² is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R² is —NR^(1a)C(O)NR^(1b), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R² is NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R² is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R² is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R² is —NR^(1a)S(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R² is —NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R² is—SR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R² is —S(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R² is —S(O)₂R^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R² is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c)are each as defined herein. In certain embodiments, R² is—S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isC₁₋₆ alkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R³ ishydrogen, methyl, ethyl, or propyl (e.g., n-propyl, isopropyl, or2-isopropyl).

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isC₁₋₆ alkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R⁴ ishydrogen, methyl, ethyl, or propyl (e.g., n-propyl, isopropyl, or2-isopropyl).

In certain embodiments, R³ and R⁴ are linked together to form a bond. Incertain embodiments, R³ and R⁴ are linked together to form C₁₋₆alkylene, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R³ and R⁴are linked together to form methylene, ethylene, or propylene, eachoptionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R³ and R⁴ are linkedtogether to form C₁₋₆ heteroalkylene, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R³ and R⁴ are linked together to form C₂₋₆ alkenylene,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R³ and R⁴ are linkedtogether to form C₂₋₆ heteroalkenylene, optionally substituted with one,two, three, four, or five substituents Q as described herein.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isC₁₋₆ alkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R⁶ is C₁₋₆alkyl, optionally substituted with one or more, in one embodiment, one,two, or three, halo. In certain embodiments, R⁶ is C₁₋₆ alkyl,optionally substituted with one or more, in one embodiment, one, two, orthree, fluoro. In certain embodiments, R⁶ is methyl, fluoromethyl,difluoromethyl, or trifluoromethyl. In certain embodiments, R⁶ isdifluoromethyl. In certain embodiments, R⁶ is —S—C₁₋₆ alkyl, wherein thealkyl is optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R⁶ is—S(O)—C₁₋₆ alkyl, wherein the alkyl is optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R⁶ is —SO₂—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein.

In certain embodiments, R^(5a) is hydrogen. In certain embodiments,R^(5a) is not hydrogen. In certain embodiments, R^(5a) is halo. Incertain embodiments, R^(5a) is fluoro, chloro, bromo, or iodo. Incertain embodiments, R^(5a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5a) is methyl, ethyl, propyl, or butyl, eachoptionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5a) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5a) is methyl. In certain embodiments, R^(5a) is C₂₋₆alkenyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R^(5a) isC₂₋₆ alkynyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R^(5a) isC₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, four, orfive substituents Q as described herein. In certain embodiments, R^(5a)is C₃₋₇ cycloalkyl, optionally substituted with one, two, three, four,or five substituents Q as described herein. In certain embodiments,R^(5a) is C₆₋₁₄ aryl, optionally substituted with one, two, three, four,or five substituents Q as described herein. In certain embodiments,R^(5a) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, R^(5a) is heteroaryl, optionally substituted with one, two,three, four, or five substituents Q as described herein. In certainembodiments, R^(5a) is heterocyclyl, optionally substituted with one,two, three, four, or five substituents Q as described herein.

In certain embodiments, R^(5a) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5a) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5a) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5a) is —C(O)OCH₃. In certain embodiments, R^(5a)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5a) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5a) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5a) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5a) a is —OS(O)₂R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5a) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5a) is —NR^(1b)R^(1c), where in R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is amino (—NH₂). In certainembodiments, R^(5a) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5a) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5a) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —NR^(1a)C(═NR¹)NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5a) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5a) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5a) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R^(5a) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5a) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5a) is —S(O)₂R^(1a), wherein R^(1d)is as defined herein. In certain embodiments, R^(5a) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,or heteroaryl, each of which is optionally substituted with one, two,three, four, or five substituents Q; or (c) —C(O)R^(1d), —C(O)OR^(1d),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR_(1a)C(O)NR^(1b)R^(1c), NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c). In certain embodiments,R^(5a) is (a) hydrogen or halo; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, or heteroaryl,each of which is optionally substituted with one, two, three, four, orfive substituents Q.

In certain embodiments, R^(5b) is halo. In certain embodiments, R^(5b)is fluoro, chloro, bromo, or iodo. In certain embodiments, R^(5b) isC₁₋₆ alkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R^(5b) ismethyl, ethyl, propyl, or butyl, each optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5b) is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, or t-butyl. In certain embodiments, R^(5b) is methyl. Incertain embodiments, R^(5b) is C₂₋₆ alkenyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5b) is C₂₋₆ alkynyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5b) is C₃₋₁₀ cycloalkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5b) is C₃₋₇ cycloalkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5b) is C₆₋₁₄ aryl,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5b) is C₇₋₁₅ aralkyl,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5b) is heteroaryl,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5b) is heterocyclyl,optionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5b) is notheterocyclyl.

In certain embodiments, R^(5b) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5b) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5b) isC(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5b) is —C(O)OCH₃. In certain embodiments, R^(5b)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5b) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5b) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5b) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5b) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5b) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5b) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is amino (—NH₂). In certainembodiments, R^(5b) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5b) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5b) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5b) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5b) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5b) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5b) is SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5b) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5b) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5b) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5a) and R^(5b) are each independently methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl, eachoptionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5a) and R^(5b) areeach independently methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, or t-butyl, each optionally substituted with one or more halo.In certain embodiments, R^(5a) and R^(5b) are each independently methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5a) and R^(5b) are each methyl.

In certain embodiments, R^(5c) is C₆₋₁₄ aryl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5b) is C₆₋₁₄ aryl substituted at the2-position with one substituent Q as described herein. In certainembodiments, R^(5c) is phenyl or naphthyl, each optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5c) is phenyl, naphtha-1-yl, or naphtha-2-yl,each optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, R^(5c) isphenyl, 4-chlorophenyl, 4-methoxyphenyl, or naphtha-2-yl. In certainembodiments, R^(5c) is heteroaryl, optionally substituted with one ormore substituents as described herein. In certain embodiments, R^(5c) ismonocyclic heteroaryl, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(5c) is 5-or 6-membered heteroaryl, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(5c) isbicyclic heteroaryl, optionally substituted with one or moresubstituents as described herein.

In certain embodiments, R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl),wherein the C₆₋₁₄ aryl is optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, R^(5c) is benzyl, 2-phenethyl, 3-phenylpropyl, or4-phenylbutyl, wherein each of the phenyl moiety is optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5c) is benzyl, 2-phenethyl,3-phenylpropyl, or 4-phenylbutyl. In certain embodiments, R^(5c) isbenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, cyanobenzyl,methylbenzyl, or methoxybenzyl. In certain embodiments, R^(5c) is(naphthalen-1-yl)methyl, (naphthalen-2-yl)methyl2-(naphthalen-1-yl)ethyl, 2-(naphthalen-2-yl)ethyl,3-(naphthalen-1-yl)propyl, 3-(naphthalen-2-yl)propyl,4-(naphthalen-1-yl)butyl, or 4-(naphthalen-2-yl)butyl, wherein each ofthe naphthyl moiety is optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, n is 0 or 1. In one embodiment, n is 1. In one embodiment,n is 1, 2, 3, or 4. In certain embodiments, R^(5c) is —CH₂—(C₆₋₁₄ aryl),wherein the C₆₋₁₄ aryl is optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, R^(5c) is —C(CH₃)₂—(C₆₋₁₄ aryl), wherein the C₆₋₁₄ aryl isoptionally substituted with one, two, three, four, or five substituentsQ as described herein. In certain embodiments, R^(5c) is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl or naphthyl is each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein, such as, e.g., optionally substituted with one or moreF, Cl, Br, I, —CN, —CH₃, —CF₃, —OCH₃, or —OCF₃. In certain embodiments,R^(5c) is —CH₂-phenyl, —CH₂-naphtha-1-yl, or —CH₂-naphtha-2-yl, whereinthe phenyl or naphthyl is each optionally substituted with one, two,three, four, or five substituents Q as described herein, such as, e.g.,optionally substituted with one or more F, Cl, Br, I, —CN, —CH₃, —CF₃,—OCH₃, or —OCF₃. In certain embodiments, R^(5c) is —CH₂-phenyl,—CH₂-naphtha-1-yl, or —CH₂-naphtha-2-yl, wherein the phenyl or naphthylis each optionally substituted with one or more F, Cl, Br, I, —CN, —CH₃,—CF₃, —OCH₃, —OCF₃. In other embodiments, R^(5c) is —CH₂-phenyl,—CH₂-naphtha-1-yl, or —CH₂-naphtha-2-yl, wherein the phenyl or naphthylis each optionally substituted with one or more F, Cl, Br, I, —CN, —CH₃,—CF₃, —OCH₃, —OCF₃, —O—(C₁₋₄ alkylene)-N—(C₁₋₄ alkyl)₂ (e.g.,—O—CH₂CH₂—N(CH₃)₂), —O-heterocyclyl (e.g., —O—(N-methylpiperidinyl) or—O-piperidinyl), —O-heteroaryl (e.g., —O-pyridyl), —NH-heterocyclyl(e.g., —N—(N-methylpiperidinyl), —NH—(N-methylpyrrolidinyl),—NH-piperidinyl, or —NH-pyrrolidinyl), —NH-heteroaryl (e.g.,—NH-pyridyl), —NCH₃-heterocyclyl (e.g., —NCH₃—(N-methylpiperidinyl),—NCH₃(N-methylpyrrolidinyl), —NCH₃-piperidinyl, or —NCH₃-pyrrolidinyl),—NCH₃-heteroaryl (e.g., —NCH₃-pyridyl), heterocyclyl (e.g., piperidinyl,piperazinyl, N-methylpiperidinyl, or N-methylpiperazinyl), or heteroaryl(e.g., pyridyl or imidazolyl). In certain embodiments, R^(5c) is—CH₂-phenyl, —C(CH₃)₂-phenyl, —CH₂-(2-methylphenyl),—CH₂-(2-methoxylphenyl), —CH₂-(2-fluorophenyl), —CH₂-(2-chlorophenyl),—CH₂-(2-bromophenyl), —CH₂-(3-methylphenyl), —CH₂-(3-methoxylphenyl),—CH₂-(3-fluorophenyl), —CH₂-(3-chlorophenyl), —CH₂-(3-bromophenyl),—CH₂-(4-methylphenyl), —CH₂-(4-methoxylphenyl), —CH₂-(4-fluorophenyl),—CH₂-(4-chlorophenyl), —CH₂-(4-bromophenyl), CH₂-naphtha-1-yl, or—CH₂-naphtha-2-yl.

In certain embodiments, R^(5c) is —(CR^(5f)R^(5g))—(C₆₋₁₄ aryl), whereinthe C₆₋₁₄ aryl is optionally substituted with one, two, three, four, orfive substituents Q as described herein, and wherein R^(5f) and R^(5g)together with the carbon atom to which they are attached form a 3- to6-membered cycloalkyl or heterocyclyl. In one embodiment, R^(5c) iscyclopropyl-phenyl. In one embodiment, R^(5c) is cyclobutyl-phenyl. Inone embodiment, R^(5c) is cyclopentyl-phenyl. In one embodiment, R^(5c)is cyclohexyl-phenyl.

In certain embodiments, R^(5c) is —(CR^(5f)R^(5g))_(n)-heteroaryl,wherein the heteroaryl is optionally substituted with one, two, three,four, or five substituents Q as described herein, wherein n is definedherein elsewhere. In certain embodiments, R^(5c) is —CH₂-(monocyclicheteroaryl), wherein the heteroaryl is optionally substituted with oneor more substituents as described herein. In certain embodiments, R^(5c)is —CH₂-(5- or 6-membered heteroaryl), wherein the heteroaryl isoptionally substituted with one or more substituents as describedherein. In certain embodiments, R^(5c) is —CH₂-(bicyclic heteroaryl),wherein the heteroaryl is optionally substituted with one or moresubstituents as described herein.

In certain embodiments, R^(5d) is hydrogen. In certain embodiments,R^(5d) is halo. In certain embodiments, R^(5d) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5d) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5d) is methyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5d) is methyl. In certainembodiments, R^(5d) is methyl, ethyl, propyl, or butyl, each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5d) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5d) is C₂₋₆ alkenyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5d) is C₂₋₆ alkynyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5d) is C₃₋₁₀ cycloalkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5d) is C₆₋₁₄ aryl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5d) is C₇₋₁₅ aralkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5d) is heteroaryl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5d) is heterocyclyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.

In certain embodiments, R^(5d) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5d) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5d) is—C(O)OR^(1a), wherein R^(1a) is —C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5d) is —C(O)OCH₃. In certain embodiments, R^(5d)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5d) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5d) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5d) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5d) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5d) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5d) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is amino (—NH₂). In certainembodiments, R^(5d) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5d) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5d) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5d) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5d) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5d) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5d) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5d) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5d) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5d) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5e) is hydrogen. In certain embodiments,R^(5e) is halo. In certain embodiments, R^(5e) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5e) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5e) is methyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5e) is methyl. In certainembodiments, R^(5e) is methyl, ethyl, propyl, or butyl, each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5e) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5e) is C₂₋₆ alkenyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5c) is C₂₋₆ alkynyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5c) is C₃₋₁₀ cycloalkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5c) is C₆₋₁₄ aryl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5c) is C₇₋₁₅ aralkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5c) is heteroaryl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5c) is heterocyclyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.

In certain embodiments, R^(5c) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5c) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5c) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5c) is —C(O)OCH₃. In certain embodiments, R^(5c)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5c) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5c) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5c) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5e) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5e) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5e) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5c) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5c) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5c) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5c) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5c) is amino (—NH₂). In certainembodiments, R^(5e) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5e) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5e) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5e) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5e) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5e) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5e) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5c) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5c) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5c) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5c) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5f) is hydrogen. In certain embodiments,R^(5f) is halo. In certain embodiments, R^(5f) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5f) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5f) is methyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5f) is methyl. In certainembodiments, R^(5f) is methyl, ethyl, propyl, or butyl, each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5f) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5f) is C₂₋₆ alkenyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5f) is C₂₋₆ alkynyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5f) is C₃₋₁₀ cycloalkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5f) is C₆₋₁₄ aryl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5f) is C₇₋₁₅ aralkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5f) is heteroaryl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5f) is heterocyclyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.

In certain embodiments, R^(5f) is 13 C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5f) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5f) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5f) is —C(O)OCH₃. In certain embodiments, R^(5f)is —C(O)NR^(1a), wherein R^(1b) and R^(1c) are each as defined herein.In certain embodiments, R^(5f) is —C(NR^(1a))NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5f) is —OR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5f) is —OC(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5f) is —OC(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5f) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5f) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5f) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5f) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is amino (—NH₂). In certainembodiments, R^(5f) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5f) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5f) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5f) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5f) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5f) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R^(5f) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5f) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5f) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5f) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5g) is hydrogen. In certain embodiments,R^(5g) is halo. In certain embodiments, R^(5g) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5g) is C₁₋₆ alkyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5g) is methyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5g) is methyl. In certainembodiments, R^(5g) is methyl, ethyl, propyl, or butyl, each optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, R^(5g) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certainembodiments, R^(5g) is C₂₋₆ alkenyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5g) is C₂₋₆ alkynyl, optionally substituted with one,two, three, four, or five substituents Q as described herein. In certainembodiments, R^(5g) is C₃₋₁₀ cycloalkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5g) is C₆₋₁₄ aryl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5g) is C₇₋₁₅ aralkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5g) is heteroaryl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, R^(5g) is heterocyclyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.

In certain embodiments, R^(5g) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5g) is —C(O)OR^(1d), whereinR^(1d) is as defined herein. In certain embodiments, R^(5g) is—C(O)OR^(1d), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, R^(5g) is —C(O)OCH₃. In certain embodiments, R^(5g)is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5g) is —OC(O)R^(1d), wherein R^(1a)is as defined herein. In certain embodiments, R^(5g) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5g) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —OS(O)R^(1d), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5g) is —OS(O)₂R^(1d), whereinR^(1d) is as defined herein. In certain embodiments, R^(5g) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5g) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is amino (NH₂). In certainembodiments, R^(5g) is NR^(1d)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5g) is—NR^(1d)C(O)OR^(1d), wherein R^(1d) and R^(1d) are each as definedherein. In certain embodiments, R^(5g) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5g) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5g) isNR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5g) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —NR^(1a)S(O)₂NR^(1b)R^(1c), where inR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5g) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5g) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5g) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5g) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, when one occurrence of R^(5f) and one occurrenceof R^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form a C₃₋₁₀cycloalkyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a C₃₋₇ cycloalkyl, optionally substitutedwith one, two, three, four, or five substituents Q as described herein.In certain embodiments, when one occurrence of R^(5f) and one occurrenceof R^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form acyclopropyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a cyclobutyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, when one occurrence of R^(5f) and one occurrence ofR^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form acyclopentyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a cyclohexyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, when one occurrence of R^(5f) and one occurrence ofR^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form acycloheptyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a cyclopropyl.

In certain embodiments, when one occurrence of R^(5f) and one occurrenceof R^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form aheterocyclyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a 3-membered heterocyclyl, optionallysubstituted with one, two, three, four, or five substituents Q asdescribed herein. In certain embodiments, when one occurrence of R^(5f)and one occurrence of R^(5g) are attached to the same carbon atom, theR^(5f) and R^(5g) together with the carbon atom to which they areattached form a 4-membered heterocyclyl, optionally substituted withone, two, three, four, or five substituents Q as described herein. Incertain embodiments, when one occurrence of R^(5f) and one occurrence ofR^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form a5-membered heterocyclyl, optionally substituted with one, two, three,four, or five substituents Q as described herein. In certainembodiments, when one occurrence of R^(5f) and one occurrence of R^(5g)are attached to the same carbon atom, the R^(5f) and R^(5g) togetherwith the carbon atom to which they are attached form a 6-memberedheterocyclyl, optionally substituted with one, two, three, four, or fivesubstituents Q as described herein.

In certain embodiments, R^(7a) is hydrogen. In certain embodiments,R^(7a) is cyano. In certain embodiments, R^(7a) is halo. In certainembodiments, R^(7a) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7a) is nitro. In certain embodiments, R^(7a) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7a) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is C₃₋₇ cycloalkyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7a) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7a) is phenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is phenyl, optionally substituted with one or more substituents, each ofwhich is selected independently from the group consisting of fluoro,chloro, bromo, methyl, and methoxy. In certain embodiments, R^(7a) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl. Incertain embodiments, R^(7a) is C₇ aralkyl, optionally substituted withone, two, three, or four substituents Q^(a) as described herein. Incertain embodiments, R^(7a) is heteroaryl, optionally substituted withone, two, three, or four substituents Q^(a) as described herein. Incertain embodiments, R^(7a) is monocyclic heteroaryl, optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(7a) is 5-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is imidazolyl or pyrozolyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7a) is imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl, or2-methylpyrozol-3-yl. In certain embodiments, R^(7a) is 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is pyridinyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, or2-methoxypyridin-4-yl. In certain embodiments, R^(7a) is heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a)as described herein. In certain embodiments, R^(7a) is monocyclicheterocyclyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7a)is 5-membered heterocyclyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7a) is 6-membered heterocyclyl, optionally substituted with one, two,three, or four substituents Q^(a) as described herein. In certainembodiments, R^(7a) is piperidinyl or piperazinyl, optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(7a) is1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7a) is —C(O)R^(a), wherein R^(a) is asdefined herein. In certain embodiments, R^(7a) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7a) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7a) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7a) is —OR^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7a) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7a) is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments, R^(7a) is —OC(O)NR^(b)R^(c), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments, R^(7a) is—OC(═NR^(a))NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7a) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7a) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7a) is —OS(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7a) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7a) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7a) is amino(—NH₂). In certain embodiments, R^(7a) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7a) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7a) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments, R^(7a) is —NR^(a)C(═NR^(d))NR^(b)R^(c), wherein R^(a),R^(b), R^(c), and R^(d) are each as defined herein. In certainembodiments, R^(7a) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) areeach as defined herein. In certain embodiments, R^(7a) is—NR^(a)S(O)₂R^(d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R^(7a) is —NR^(a)S(O)NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7a) is —NR^(a)S(O)₂NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) areeach as defined herein. In certain embodiments, R^(7a) is —SR^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7a) is—S(O)R^(a), wherein R^(a) is as defined herein. In certain embodiments,R^(7a) is —S(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7a) is —S(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7a) is—S(O)₂NR^(b)R^(c); wherein R^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7a) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7a) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7b) is hydrogen. In certain embodiments,R^(7b) is cyano. In certain embodiments, R^(7b) is halo. In certainembodiments, R^(7b) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7b) is nitro. In certain embodiments, R^(7b) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7b) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7b)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7b)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7b) is C₃₋₇ cycloalkyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7b) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7b) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7b) is heteroaryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7b) is heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein.

In certain embodiments, R^(7b) is —C(O)R^(a), wherein R^(a) is asdefined herein. In certain embodiments, R^(7b) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7b) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7b) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7b) is —OR^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7b) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7b) is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments, R^(7b) is —OC(O)NR^(b)R^(c), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments, R^(7b) is—OC(═NR^(a))NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7b) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7b) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7b) is —OS(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7b) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7b) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7b) is amino(—NH₂). In certain embodiments, R^(7b) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7b) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7b) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments, R^(7b) is —NR^(a)C(═NR^(d))NR^(b)R^(c), wherein R^(a),R^(b), R^(c), and R^(d) are each as defined herein. In certainembodiments, R^(7b) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) areeach as defined herein. In certain embodiments, R^(7b) is—NR^(d)S(O)₂R^(d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R^(7b) is —NR^(d)S(O)NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7b) is —NR^(a)S(O)₂NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) areeach as defined herein. In certain embodiments, R^(7b) is —SR^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7b) is—S(O)R^(a), wherein R^(a) is as defined herein. In certain embodiments,R^(7b) is —S(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7b) is —S(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7b) is—S(O)₂NR^(b)R^(c); wherein R^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7b) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7b) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7c) is hydrogen. In certain embodiments,R^(7c) is cyano. In certain embodiments, R^(7c) is halo. In certainembodiments, R^(7c) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7c) is nitro. In certain embodiments, R^(7c) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7c) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7c)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7c)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7c) is C₃₋₇ cycloalkyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7c) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7c) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7c) is heteroaryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7c) is heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein.

In certain embodiments, R^(7c) is —C(O)R^(d), wherein R^(a) is asdefined herein. In certain embodiments, R^(7c) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7c) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7c) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7c) is —OR^(d), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7c) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7c) is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments, R^(7c) is —OC(O)NR^(b)R^(c), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments, R^(7c) is—OC(═NR^(a))NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7c) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7c) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7c) is —OS(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7c) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7c) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7c) is amino(—NH₂). In certain embodiments, R^(7c) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7c) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7c) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments, R^(7c) is —NR^(a)C(═NR^(d))NR^(b)R^(c), wherein R^(a),R^(b), R^(c), and R^(d) are each as defined herein. In certainembodiments, R^(7c) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) areeach as defined herein. In certain embodiments, R^(7c) is—NR^(a)S(O)₂R^(d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R^(7c) is —NR^(a)S(O)NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7c) is —NR^(a)S(O)₂NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) areeach as defined herein. In certain embodiments, R^(7c) is —SR^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7c) is—S(O)R^(a), wherein R^(a) is as defined herein. In certain embodiments,R^(7c) is —S(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7c) is —S(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7c) is—S(O)₂NR^(b)R^(c); wherein R^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7c) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7c) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7d) is hydrogen. In certain embodiments,R^(7d) is cyano. In certain embodiments, R^(7d) is halo. In certainembodiments, R^(7d) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7d) is nitro. In certain embodiments, R^(7d) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7d) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7d)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7d)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7d) is C₃₋₇ cycloalkyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7d) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7d) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7d) is heteroaryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7d) is heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein.

In certain embodiments, R^(7d) is —C(O)R^(a), wherein R^(a) is asdefined herein. In certain embodiments, R^(7d) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7d) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7d) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7d) is —OR^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7d) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7d) is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments, R^(7d) is —OC(O)NR^(b)R^(c), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments, R^(7d) is—OC(═NR^(a))NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7d) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7d) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7d) is —OS(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7d) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7d) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7d) is amino(—NH₂). In certain embodiments, R^(7d) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7d) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7d) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments, R^(7d) is —NR^(a)C(═NR^(d))NR^(b)R^(c), wherein R^(a),R^(b), R^(c), and R^(d) are each as defined herein. In certainembodiments, R^(7d) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) areeach as defined herein. In certain embodiments, R^(7d) is—NR^(a)S(O)₂R^(d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R^(7d) is —NR^(a)S(O)NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7d) is —NR^(a)S(O)₂NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) areeach as defined herein. In certain embodiments, R^(7d) is —SR^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7d) is—S(O)R^(a), wherein R^(a) is as defined herein. In certain embodiments,R^(7d) is —S(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7d) is —S(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7d) is—S(O)₂NR^(b)R^(c); wherein R^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7d) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7d) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7e) is hydrogen. In certain embodiments,R^(7e) is cyano. In certain embodiments, R^(7e) is halo. In certainembodiments, R^(7e) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7e) is nitro. In certain embodiments, R^(7e) is C₁₋₆alkyl, optionally substituted with one, two, three, or four substituentsQ^(a) as described herein. In certain embodiments, R^(7c) is C₂₋₆alkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7e)is C₂₋₆ alkynyl, optionally substituted with one, two, three, or foursubstituents Q^(a) as described herein. In certain embodiments, R^(7e)is C₃₋₁₀ cycloalkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7e) is C₃₋₇ cycloalkyl, optionally substituted with one, two, three,or four substituents Q^(a) as described herein. In certain embodiments,R^(7e) is C₆₋₁₄ aryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7e) is C₇₋₁₅ aralkyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7c) is heteroaryl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein. In certain embodiments,R^(7e) is heterocyclyl, optionally substituted with one, two, three, orfour substituents Q^(a) as described herein.

In certain embodiments, R^(7e) is —C(O)R^(a), wherein R^(a) is asdefined herein. In certain embodiments, R^(7e) is —C(O)OR^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7c) is—C(O)NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein. Incertain embodiments, R^(7e) is —C(NR^(a))NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7e) is —OR^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(a) is —O—C₁₋₆ alkyl, wherein the alkyl is optionallysubstituted with one, two, three, or four substituents Q^(a) asdescribed herein. In certain embodiments, R^(a) is methoxy, ethoxy,propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments,R^(7c) is —OC(O)R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7c) is —OC(O)OR^(a), wherein R^(a) is as defined herein.In certain embodiments, R^(7e) is —OC(O)NR^(b)R^(c), wherein R^(b) andR^(c) are each as defined herein. In certain embodiments, R^(7c) is—OC(═NR^(a))NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) are each asdefined herein. In certain embodiments, R^(7e) is —OS(O)R^(a), whereinR^(a) is as defined herein. In certain embodiments, R^(7e) is—OS(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7c) is —OS(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7e) is—OS(O)₂NR^(b)R^(c), wherein R^(b) and R^(c) are each as defined herein.In certain embodiments, R^(7c) is —NR^(b)R^(c), wherein R^(b) and R^(c)are each as defined herein. In certain embodiments, R^(7e) is amino(—NH₂). In certain embodiments, R^(7c) is —NR^(a)C(O)R^(d), whereinR^(a) and R^(d) are each as defined herein. In certain embodiments,R^(7c) is —NR^(a)C(O)OR^(d), wherein R^(a) and R^(d) are each as definedherein. In certain embodiments, R^(7c) is —NR^(a)C(O)NR^(b)R^(c),wherein R^(a), R^(b), and R^(c) are each as defined herein. In certainembodiments, R^(7c) is —NR^(a)C(═NR^(d))NR^(b)R^(c), wherein R^(a),R^(b), R^(c), and R^(d) are each as defined herein. In certainembodiments, R^(7e) is —NR^(a)S(O)R^(d), wherein R^(a) and R^(d) areeach as defined herein. In certain embodiments, R^(7e) is—NR^(a)S(O)₂R^(d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R^(7e) is —NR^(a)S(O)NR^(b)R^(c), wherein R^(a),R^(b), and R^(c) are each as defined herein. In certain embodiments,R^(7e) is —NR^(a)S(O)₂NR^(b)R^(c), wherein R^(a), R^(b), and R^(c) areeach as defined herein. In certain embodiments, R^(7e) is —SR^(a),wherein R^(a) is as defined herein. In certain embodiments, R^(7e) is—S(O)R^(a), wherein R^(a) is as defined herein. In certain embodiments,R^(7e) is —S(O)₂R^(a), wherein R^(a) is as defined herein. In certainembodiments, R^(7e) is —S(O)NR^(b)R^(c), wherein R^(b) and R^(c) areeach as defined herein. In certain embodiments, R^(7e) is—S(O)₂NR^(b)R^(c); wherein R^(b) and R^(c) are each as defined herein.

In certain embodiments, R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7a) and R^(7b) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a). In certain embodiments, R^(7a) andR^(7b) together with the carbon atoms to which they are attached formC₃₋₁₀ cycloalkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form cyclohexenyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7a) and R^(7b) together with the carbon atomsto which they are attached form C₆₋₁₄ aryl, optionally substituted withone, two, three, or four substituents Q^(a). In certain embodiments,R^(7a) and R^(7b) together with the carbon atoms to which they areattached form phenyl, optionally substituted with one, two, three, orfour substituents Q^(a). In certain embodiments, R^(7a) and R^(7b)together with the carbon atoms to which they are attached formheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form monocyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q. In certain embodiments, R^(7a) and R^(7b) together withthe carbon atoms to which they are attached form bicyclic heteroaryl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7a) and R^(7b) together with the carbon atomsto which they are attached form heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a). In certainembodiments, R^(7a) and R^(7b) together with the carbon atoms to whichthey are attached form monocyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a). In certainembodiments, R^(7a) and R^(7b) together with the carbon atoms to whichthey are attached form 5- or 6-membered heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7a) and R^(7b) together with the carbon atoms to whichthey are attached form bicyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a).

In certain embodiments, R^(7b) and R^(7c) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a). In certain embodiments, R^(b) andR^(7c) together with the carbon atoms to which they are attached formC₃₋₁₀ cycloalkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form cyclohexenyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7b) and R^(7c) together with the carbon atomsto which they are attached form C₆₋₁₄ aryl, optionally substituted withone, two, three, or four substituents Q^(a). In certain embodiments,R^(7b) and R^(7c) together with the carbon atoms to which they areattached form phenyl, optionally substituted with one, two, three, orfour substituents Q^(a). In certain embodiments, R^(7b) and R^(7c)together with the carbon atoms to which they are attached formheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form monocyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q. In certain embodiments, R^(7b) and R^(7c) together withthe carbon atoms to which they are attached form bicyclic heteroaryl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7b) and R^(7c) together with the carbon atomsto which they are attached form heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a). In certainembodiments, R^(7b) and R^(7c) together with the carbon atoms to whichthey are attached form monocyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a). In certainembodiments, R^(7b) and R^(7c) together with the carbon atoms to whichthey are attached form 5- or 6-membered heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7b) and R^(7c) together with the carbon atoms to whichthey are attached form bicyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a).

In certain embodiments, R^(7c) and R^(7d) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a). In certain embodiments, R^(7c) andR^(7d) together with the carbon atoms to which they are attached formC₃₋₁₀ cycloalkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form cyclohexenyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7c) and R^(7d) together with the carbon atomsto which they are attached form C₆₋₁₄ aryl, optionally substituted withone, two, three, or four substituents Q^(a). In certain embodiments,R^(7c) and R^(7d) together with the carbon atoms to which they areattached form phenyl, optionally substituted with one, two, three, orfour substituents Q^(a). In certain embodiments, R^(7c) and R^(7d)together with the carbon atoms to which they are attached formheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form monocyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form bicyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7c) and R^(7d) together with the carbon atomsto which they are attached form monocyclic heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7c) and R^(7d) together with the carbon atoms to whichthey are attached form 5- or 6-membered heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7c) and R^(7d) together with the carbon atoms to whichthey are attached form bicyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a).

In certain embodiments, R^(7d) and R^(7e) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a). In certain embodiments, R^(7d) andR^(7e) together with the carbon atoms to which they are attached formC₃₋₁₀ cycloalkenyl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form cyclohexenyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7d) and R^(7e) together with the carbon atomsto which they are attached form C₆₋₁₄ aryl, optionally substituted withone, two, three, or four substituents Q^(a). In certain embodiments,R^(7d) and R^(7e) together with the carbon atoms to which they areattached form phenyl, optionally substituted with one, two, three, orfour substituents Q^(a). In certain embodiments, R^(7d) and R^(7e)together with the carbon atoms to which they are attached formheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form monocyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form bicyclicheteroaryl, optionally substituted with one, two, three, or foursubstituents Q^(a). In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form heterocyclyl,optionally substituted with one, two, three, or four substituents Q^(a).In certain embodiments, R^(7d) and R^(7e) together with the carbon atomsto which they are attached form monocyclic heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7d) and R^(7e) together with the carbon atoms to whichthey are attached form 5- or 6-membered heterocyclyl, optionallysubstituted with one, two, three, or four substituents Q^(a). In certainembodiments, R^(7d) and R^(7e) together with the carbon atoms to whichthey are attached form bicyclic heterocyclyl, optionally substitutedwith one, two, three, or four substituents Q^(a).

In certain embodiments, m is 0. In certain embodiments, m is 1.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2. In certain embodiments, n is 3. In certainembodiments, n is 4. In certain embodiments, n is 0, 1, or 2. In certainembodiments, n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or3. In certain embodiments, n is 1 or 2.

In certain embodiments, m is 0, and n is 0, 1, 2, or 3. In certainembodiments, m is 0, n is 0, 1, or 2. In certain embodiments, m is 0,and n is 0 or 1. In certain embodiments, m is 0, and n is 0. In certainembodiments, m is 0, and n is 1. In certain embodiments, m is 1, and nis 0, 1, 2, or 3. In certain embodiments, m is 1, and n is 0, 1, or 2.In certain embodiments, m is 1, and n is 0 or 1. In certain embodiments,m is 1, and n is 0. In certain embodiments, m is 1, and n is 1.

In specific embodiments, m is 0, n is 1, and R^(5a) and R^(5b) are eachmethyl.

In certain embodiments, X is N In certain embodiments, X is CR^(x),wherein R^(x) is as defined herein. In certain embodiments, X is CH.

In certain embodiments, Y is N In certain embodiments, Y is CR^(x),wherein R^(x) is as defined herein. In certain embodiments, Y is CH.

In certain embodiments, Z is N In certain embodiments, Z is CR^(x),wherein R^(x) is as defined herein. In certain embodiments, Z is CH.

In certain embodiments, X, Y, and Z are N. In certain embodiments, X andY are N, and Z is CH. In certain embodiments, X and Z are N, and Y isCH. In certain embodiments, Y and Z are N, and X is CH.

In certain embodiments, the compound provided herein is not4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(2-phenyl-2-(pyrrolidin-1-ypethyl)-1,3,5-triazin-2-amine.In certain embodiments, the compound provided herein is not6-(2-(difluoromethyl)-1H-benzoldlimidazol-1-yl)-N-(1-(4-((R)-3-(methoxymethyl)morpholino)phenyl)ethyl)-2-morpholinopyrimidin-4-amine.

In certain embodiments, when X, Y, and Z are N, and R^(5a) is hydrogen,R^(5b) is not heterocyclyl. In certain embodiments, when X, Y, and Z areN, and R^(5a) is hydrogen, R^(5b) is not 5-membered heterocyclyl. Incertain embodiments, when X, Y, and Z are N, and R^(5a) is hydrogen,R^(5b) is not pyrrolidinyl. In certain embodiments, when X, Y, and Z areN, and R^(5a) is hydrogen, R^(5b) is not pyrrolidin-1-yl.

In certain embodiments, when X and Z are N, Y is CH, and R^(5a) ishydrogen, R^(5b) is morpholino-substituted phenyl. In certainembodiments, when X and Z are N, Y is CH, and R^(5a) is hydrogen, R^(5b)is not 4-((R)-3-(methoxymethyl)morpholino)phenyl.

In one embodiment, provided herein is a compound selected from:

In one embodiment, the PI3K inhibitor is Compound A35, isotopicvariants, pharmaceutically acceptable salts, solvates, hydrates, andprodrugs thereof. In one embodiment, the PI3K inhibitor is Compound A36,isotopic variants, pharmaceutically acceptable salts, solvates,hydrates, and prodrugs thereof. In one embodiment, the PI3K inhibitor isCompound A68, isotopic variants, pharmaceutically acceptable salts,solvates, hydrates, and prodrugs thereof. In one embodiment, the PI3Kinhibitor is Compound A70, isotopic variants, pharmaceuticallyacceptable salts, solvates, hydrates, and prodrugs thereof. In oneembodiment, the PI3K inhibitor is Compound A37, isotopic variants,pharmaceutically acceptable salts, solvates, hydrates, and prodrugsthereof. In one embodiment, the PI3K inhibitor is Compound A38, isotopicvariants, pharmaceutically acceptable salts, solvates, hydrates, andprodrugs thereof. In one embodiment, the PI3K inhibitor is Compound A41,isotopic variants, pharmaceutically acceptable salts, solvates,hydrates, and prodrugs thereof. In one embodiment, the PI3K inhibitor isCompound A42, isotopic variants, pharmaceutically acceptable salts,solvates, hydrates, and prodrugs thereof. In one embodiment, the PI3Kinhibitor is Compound A43, isotopic variants, pharmaceuticallyacceptable salts, solvates, hydrates, and prodrugs thereof. In oneembodiment, the PI3K inhibitor is Compound A44, isotopic variants,pharmaceutically acceptable salts, solvates, hydrates, and prodrugsthereof. In one embodiment, the PI3K inhibitor is Compound A62, isotopicvariants, pharmaceutically acceptable salts, solvates, hydrates, andprodrugs thereof. In one embodiment, the PI3K inhibitor is Compound A63,isotopic variants, pharmaceutically acceptable salts, solvates,hydrates, and prodrugs thereof. In one embodiment, the PI3K inhibitor isCompound A64, isotopic variants, pharmaceutically acceptable salts,solvates, hydrates, and prodrugs thereof. In one embodiment, the PI3Kinhibitor is Compound A65, isotopic variants, pharmaceuticallyacceptable salts, solvates, hydrates, and prodrugs thereof. In oneembodiment, the PI3K inhibitor is Compound A66, isotopic variants,pharmaceutically acceptable salts, solvates, hydrates, and prodrugsthereof. In one embodiment, the PI3K inhibitor is Compound A67, isotopicvariants, pharmaceutically acceptable salts, solvates, hydrates, andprodrugs thereof.

Synthesis of compounds of any of the Formulae provided herein, e.g.,Formulae (I), (IX), (X), (XI), and/or (XVI), is described in U.S. Pat.No. 9,056,852 B2, which is incorporated by reference for suchdisclosure.

CD20 Inhibitors

Described herein are PI3K inhibitors in combination with CD20inhibitors.

B lymphocytes are the origin of humoral immunity, represent asubstantial portion of hematopoietic malignancies, and contribute toautoimmunity. Consequently, cell surface molecules expressed by B cellsand their malignant counterparts are important targets forimmunotherapy. CD20, a B cell-specific member of the MS4A gene family,is expressed on the surface of immature and mature B cells and theirmalignant counterparts.

A limited analysis of CD20 transcripts in mouse cell lines and tissuessuggests that mouse CD20 is also B cell-specific. Both human and mouseCD20 cDNAs encode a membrane-embedded protein with hydrophobic regionsof sufficient length to pass through the membrane four times. Mouse andhuman CD20 are well conserved (73%) in amino acid sequence, particularlythe transmembrane and long amino- and carboxyl-terminal cytoplasmicdomains. The cytoplasmic domains are serine- and threonine-rich withmultiple consensus sequences for phosphorylation. Human CD20 is notglycosylated, but three isoforms (33-, 35- and 37,000 Mr) result fromthe differential phosphorylation of a single protein on different serineand threonine residues.

CD20 plays a role in the regulation of human B cell activation,proliferation, and Ca²⁺ transport. Antibody ligation of CD20 cangenerate transmembrane signals that result in enhanced CD20phosphorylation, induction of c-myc and B-myb oncogene expression,induced serine/threonine and tyrosine phosphorylation of cellularproteins, increased CD18, CD58 and MHC class II molecule expression, andprotein tyrosine kinase activation that induces B cell adhesion. CD20ligation promotes transmembrane Ca²⁺ transport, but does not usuallylead to increased intracellular calcium ([Ca²⁺]_(i))₃ levels, exceptafter extensive crosslinking. Antibody binding to CD20 inhibits B cellprogression from the G1 phase into the S/G2+M stages of cell cyclefollowing mitogen stimulation, and inhibits mitogen-induced B celldifferentiation and antibody secretion. Extensive CD20 cross-linking canalso influence apoptosis. These divergent observations may be explainedin part by the finding that CD20 is a component of an oligomeric complexthat forms a membrane transporter or Ca²⁺ ion channel that is activatedduring cell cycle progression. Despite this, B cell development andfunction in a line of CD20-deficient (CD20−/−) mice is reported to benormal.

The majority of human B cell-lineage malignancies express CD20. Chimericor radiolabeled monoclonal antibody-based therapies directed againstCD20 have been used for B cell malignancies such as non-Hodgkin'slymphoma.

Any suitable CD20 inhibitor may be used in combination with a PI3Kinhibitor described herein. In some embodiments, the CD20 inhibitor isan antagonist of CD20. In some embodiments, the CD20 inhibitor is anantibody, variant, or biosimilar thereof. In some embodiments, the CD20inhibitor is a monoclonal antibody.

Some embodiments provided herein describe a pharmaceutical compositionsor methods for using the pharmaceutical compositions comprising a PI3Kinhibitor described herein in combination with a CD20 inhibitor. CD20inhibitors for use in pharmaceutical compositions and methods providedherein include but are not limited to ofatumumab, obinutuzumab,rituximab, ocaratuzumab, ocrelizumab, tositumomab, ibritumomab tiuxetan,tisotumab vedotin, ublituximab, TRU-015, veltuzumab, BTCT4465A (RG7828),EDC9, MT-3724, BLX-301, 1 F5, ATCC deposit HB-96450, BM-ca, C2H7,PRO131921, BVX-20, MEDI-522, or a variant or biosimilar thereof, orcombinations thereof. In some embodiments, the CD20 inhibitor for use inpharmaceutical compositions and methods provided herein is ofatumumab,obinutuzumab, rituximab, ocaratuzumab, ocrelizumab, tositumomab,ibritumomab tiuxetan, tisotumab vedotin, ublituximab, TRU-015,veltuzumab, BTCT4465A (RG7828), EDC9, MT-3724, or a variant orbiosimilar thereof, or combinations thereof. In some embodiments, theCD20 inhibitor for use in pharmaceutical compositions and methodsprovided herein is ofatumumab, obinutuzumab, rituximab, ocaratuzumab,ocrelizumab, tositumomab, ibritumomab tiuxetan, tisotumab vedotin,ublituximab, veltuzumab, or a variant or biosimilar thereof, orcombinations thereof. In some embodiments, the CD20 inhibitor for use inpharmaceutical compositions and methods provided herein is obinutuzumabor rituximab, or a variant or biosimilar thereof, or combinationsthereof.

In some embodiments, the CD20 inhibitor is ofatumumab, an ofatumumabvariant, or an ofatumumab biosimilar. In some embodiments, the CD20inhibitor is obinutuzumab, an obinutuzumab variant, or an obinutuzumabbiosimilar. In some embodiments, the CD20 inhibitor is rituximab, arituximab variant, or a rituximab biosimilar. In some embodiments, therituximab biosimilar is CT-P10, Reditux®, ABP 798, AcellBia, BI 695500,Maball, JHL1101, Novex, MabionCD20, PF-05280586, Kikuzubam, SAIT101, GP2013, HLX01, CMAB304, BT-D004, AP-052 or TL-011. In some embodiments,the CD20 inhibitor is ocaratuzumab, an ocaratuzumab variant, or anocaratuzumab biosimilar. In some embodiments, the CD20 inhibitor isocrelizumab, an ocrelizumab variant, or an ocrelizumab biosimilar. Insome embodiments, the CD20 inhibitor is tositumomab, a tositumomabvariant, or a tositumomab biosimilar. In some embodiments, the CD20inhibitor is ibritumomab tiuxetan, an ibritumomab tiuxetan variant, oran ibritumomab tiuxetan biosimilar. In some embodiments, the CD20inhibitor is tisotumab vedotin, a tisotumab vedotin variant, or atisotumab vedotin biosimilar. In some embodiments, the CD20 inhibitor isublituximab, an ublituximab variant, or an ublituximab biosimilar. Insome embodiments, the CD20 inhibitor is TRU-015, a TRU-015 variant, or aTRU-015 biosimilar. In some embodiments, the CD20 inhibitor isveltuzumab, a veltuzumab variant, or a veltuzumab biosimilar. In someembodiments, the CD20 inhibitor is BTCT4465A (RG7828), a BTCT4465A(RG7828) variant, or a BTCT4465A (RG7828) biosimilar. In someembodiments, the CD20 inhibitor is EDC9, an EDC9 variant, or an EDC9biosimilar. In some embodiments, the CD20 inhibitor is MT-3724, aMT-3724 variant, or a MT-3724 biosimilar.

Methods of Use

Idelalisib is a PI3K inhibitor studied for relapsed chronic lymphocyticleukemia (CLL) in combination with rituximab. However, the combinationof idelalisib and a CD20 inhibitor (e.g., rituximab or ofatumumab) hasdemonstrated an alarming increase in the risk of death due to infectionand/or severe adverse effects, limiting the utility of the combination.Undesirable effects observed include but are not limited to infections,neutropenia, diarrhea/colitis, elevated liver transaminases (alanineaminotransferase/aspartate aminotransferase >5× upper limit of normal),pneumonitis, rash, hepatic impairment, renal impairment, pyrexia,increased triglycerides, or combinations thereof. Combinations of a PI3Kinhibitor and a CD20 inhibitor with reduced side effects are needed toeffectively treat cancers described herein (e.g., CLL).

Some embodiments provided herein describe a method for treating orpreventing a proliferative disease or disorder comprising administeringa PI3K inhibitor in combination with a CD20 inhibitor. In someembodiments provided herein is a method for preventing relapse of aproliferative disease or disorder, the method comprising administering aPI3K inhibitor in combination with a CD20 inhibitor. In some embodimentsprovided herein is a method for achieving and retaining partial cancerremission, the method comprising administering a PI3K inhibitor incombination with a CD20 inhibitor. In some embodiments provided hereinis a method for achieving and retaining complete cancer remission, themethod comprising administering a PI3K inhibitor in combination with aCD20 inhibitor. In some embodiments, the combination therapy of a PI3Kinhibitor described herein (e.g., a compound of Formula (I)) and a CD20inhibitor provides a synergistic effect. In some embodiments, thecombination therapy of a PI3K inhibitor described herein (e.g., acompound of Formula (I)) and a CD20 inhibitor provides a synergisticantitumor or anti-cancer activity. In certain embodiments, thecombination therapy described herein permits the use of lower dosages ofthe PI3K inhibitor and/or the CD20 inhibitor. In some embodiments, thecombination therapy described herein permits less frequentadministration of the PI3K inhibitor and/or the CD20 inhibitor to asubject. In some embodiments, the combination therapy described hereinreduces the toxicity associated with the administration of the PI3Kinhibitor and/or the CD20 inhibitor to a subject without reducing theefficacy in the prevention, management, treatment, or amelioration ofcancer, such as a B cell malignancy. In some embodiments, thesynergistic effect observed with the combination therapy describedherein results in improved efficacy of therapies in the prevention,management, treatment, or amelioration of cancer, such as a B cellmalignancy.

In some embodiments, the combination therapy described herein avoids orreduces adverse or unwanted side effects associated with the use of thePI3K inhibitor and/or the CD20 inhibitor. In some embodiments, thecombination therapy described herein avoids, reduces, or minimizes therisk of death due to infections. In some embodiments, the combinationtherapy described herein avoids, reduces, or minimizes infections,neutropenia, diarrhea/colitis, elevated liver transaminases (alanineaminotransferase/aspartate aminotransferase >5× upper limit of normal),pneumonitis, rash, hepatic impairment, renal impairment, pyrexia, orincreased triglycerides, or a combination thereof in patients receivingthe combination therapy. In certain embodiments, the combination therapydescribed herein avoids, reduces, or minimizes the incidence ofinfection associated with the use of the PI3K inhibitor and/or the CD20inhibitor. In certain embodiments, the combination therapy describedherein avoids, reduces, or minimizes the incidence of neutropenia. Incertain embodiments, the combination therapy described herein avoids,reduces, or minimizes the incidence of diarrhea/colitis. In certainembodiments, the combination therapy described herein avoids, reduces,or minimizes the incidence of elevated liver transaminases. In certainembodiments, the combination therapy described herein avoids, reduces,or minimizes the incidence of pneumonitis. In certain embodiments, thecombination therapy described herein avoids, reduces, or minimizes theincidence of a rash. In certain embodiments, the combination therapydescribed herein avoids, reduces, or minimizes the incidence of hepaticimpairment or renal impairment. In certain embodiments, the combinationtherapy described herein avoids, reduces, or minimizes the incidence ofpyrexia. In certain embodiments, the combination therapy describedherein avoids, reduces, or minimizes the incidence of increasedtriglycerides. In certain embodiments, the combination therapy describedherein avoids, reduces, or minimizes enterocolitis (manifested asdiarrhea), cutaneous toxicities, liver toxicity (manifested as elevationof transaminases), pulmonary toxicity (manifested as non-infectiouspneumonitis), infections, or combinations thereof.

In some embodiments, the combination therapy described herein provides ahigh objective response rate (ORR) as determined by tumor assessmentfrom radiological tests and/or physical examination. In someembodiments, the combination therapy described herein provides a durableresponse (DR) and/or increased durable response rate (DRR; a continuousresponse [complete or partial objective response] beginning within 12months of treatment and lasting ≥6 months) in the subject or patient. Insome embodiments, the combination therapy described herein providescomplete remission. In some embodiments, the combination therapydescribed herein provides a better response compared to the monotherapytreatment of a compound of formula (I) and/or a CD20 inhibitor. In someembodiments, the combination therapy described herein provides completeremission beginning within 12 months of treatment and lasting ≥6 months.In some embodiments, the combination therapy described herein provides acomplete response (CR) and/or no evidence of disease (NED) beginningwithin 12 months of treatment and lasting ≥6 months.

In certain embodiments, provided herein are methods for treating orpreventing a disease comprising administering an effective amount of acompound of Formula (I), or an isotopic variant thereof or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand an effective amount of a CD20 inhibitor. In some embodiments, thecompound of Formula (I) is Compound A35 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In some embodiments, the compound of Formula (I) is Compound A36 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In some embodiments, the compound of Formula (I) isCompound A68 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof. In some embodiments, the compoundof Formula (I) is Compound A70 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound A37 or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is CompoundA38 or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound A41 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound A42 or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is CompoundA43 or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound A44 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound A62 or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is CompoundA63 or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound A64 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the compound of Formula (I) is Compound A65 or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In some embodiments, the compound of Formula (I) is CompoundA66 or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof. In some embodiments, the compound ofFormula (I) is Compound A67 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the CD20 inhibitor is ofatumumab, obinutuzumab, rituximab,ocaratuzumab, ocrelizumab, tositumomab, ibritumomab tiuxetan, tisotumabvedotin, ublituximab, TRU-015, veltuzumab, BTCT4465A (RG7828), EDC9,MT-3724, or a variant or biosimilar thereof. In some embodiments, theCD20 inhibitor is rituximab.

In some embodiments, the compound of Formula (I) is Compound A35 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is rituximab, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A35 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isobinutuzumab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A35 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is ofatumumab, or a variant, or biosimilarthereof. In some embodiments, the compound of Formula (I) is CompoundA35 or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and the CD20 inhibitor is ocaratuzumab, or avariant, or biosimilar thereof. In some embodiments, the compound ofFormula (I) is Compound A35 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof and the CD20inhibitor is tositumomab, or a variant, or biosimilar thereof. In someembodiments, the compound of Formula (I) is Compound A35 or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof and the CD20 inhibitor is ibritumomab tiuxetan, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A35 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isublituximab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A35 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is EDC9, or a variant, or biosimilar thereof. Insome embodiments, the compound of Formula (I) is Compound A35 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is MT-3724, or a variant, orbiosimilar thereof.

In some embodiments, the compound of Formula (I) is Compound A36 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is rituximab, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A36 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isobinutuzumab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A36 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is ofatumumab, or a variant, or biosimilarthereof. In some embodiments, the compound of Formula (I) is CompoundA36 or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and the CD20 inhibitor is ocaratuzumab, or avariant, or biosimilar thereof. In some embodiments, the compound ofFormula (I) is Compound A36 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof and the CD20inhibitor is tositumomab, or a variant, or biosimilar thereof. In someembodiments, the compound of Formula (I) is Compound A36 or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof and the CD20 inhibitor is ibritumomab tiuxetan, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A36 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isublituximab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A36 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is EDC9, or a variant, or biosimilar thereof. Insome embodiments, the compound of Formula (I) is Compound A36 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is MT-3724, or a variant, orbiosimilar thereof.

In some embodiments, the compound of Formula (I) is Compound A68 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is rituximab, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A68 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isobinutuzumab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A68 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is ofatumumab, or a variant, or biosimilarthereof. In some embodiments, the compound of Formula (I) is CompoundA68 or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and the CD20 inhibitor is ocaratuzumab, or avariant, or biosimilar thereof. In some embodiments, the compound ofFormula (I) is Compound A68 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof and the CD20inhibitor is tositumomab, or a variant, or biosimilar thereof. In someembodiments, the compound of Formula (I) is Compound A68 or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof and the CD20 inhibitor is ibritumomab tiuxetan, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A68 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isublituximab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A68 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is EDC9, or a variant, or biosimilar thereof. Insome embodiments, the compound of Formula (I) is Compound A68 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is MT-3724, or a variant, orbiosimilar thereof.

In some embodiments, the compound of Formula (I) is Compound A70 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is rituximab, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A70 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isobinutuzumab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A70 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is ofatumumab, or a variant, or biosimilarthereof. In some embodiments, the compound of Formula (I) is CompoundA70 or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and the CD20 inhibitor is ocaratuzumab, or avariant, or biosimilar thereof. In some embodiments, the compound ofFormula (I) is Compound A70 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof and the CD20inhibitor is tositumomab, or a variant, or biosimilar thereof. In someembodiments, the compound of Formula (I) is Compound A70 or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof and the CD20 inhibitor is ibritumomab tiuxetan, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A70 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isublituximab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A70 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is EDC9, or a variant, or biosimilar thereof. Insome embodiments, the compound of Formula (I) is Compound A70 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is MT-3724, or a variant, orbiosimilar thereof.

In some embodiments, the compound of Formula (I) is Compound A37 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is rituximab, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A37 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isobinutuzumab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A37 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is ofatumumab, or a variant, or biosimilarthereof. In some embodiments, the compound of Formula (I) is CompoundA37 or an isotopic variant, pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and the CD20 inhibitor is ocaratuzumab, or avariant, or biosimilar thereof. In some embodiments, the compound ofFormula (I) is Compound A37 or an isotopic variant, pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof and the CD20inhibitor is tositumomab, or a variant, or biosimilar thereof. In someembodiments, the compound of Formula (I) is Compound A37 or an isotopicvariant, pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof and the CD20 inhibitor is ibritumomab tiuxetan, or a variant, orbiosimilar thereof. In some embodiments, the compound of Formula (I) isCompound A37 or an isotopic variant, pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and the CD20 inhibitor isublituximab, or a variant, or biosimilar thereof. In some embodiments,the compound of Formula (I) is Compound A37 or an isotopic variant,pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor is EDC9, or a variant, or biosimilar thereof. Insome embodiments, the compound of Formula (I) is Compound A37 or anisotopic variant, pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and the CD20 inhibitor is MT-3724, or a variant, orbiosimilar thereof.

In some embodiments, the proliferative disease is cancer. In certainembodiments, the proliferative disease is a hematological malignancy.

In certain embodiments, the cancer treatable with the methods providedherein includes, but is not limited to, (1) leukemias, including, butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplasticsyndrome or a symptom thereof (such as anemia, thrombocytopenia,neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RAwith ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB intransformation (RAEB-T), preleukemia, and chronic myelomonocyticleukemia (CMML), (2) chronic leukemias, including, but not limited to,chronic myelocytic (granulocytic) leukemia, chronic lymphocyticleukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas,including, but not limited to, Hodgkin's disease and non-Hodgkin'sdisease; (5) multiple myelomas, including, but not limited to,smoldering multiple myeloma, non-secretory myeloma, osteoscleroticmyeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullaryplasmacytoma; (6) Waldenstrom's macroglobulinernia; (7) monoclonalgammopathy of undetermined significance; (8) benign monoclonalgammopathy; (9) heavy chain disease; (10) bone and connective tissuesarcomas, including, but not limited to, bone sarcoma, osteosarcoma,chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor,fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastaticcancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11)brain tumors, including, but not limited to, glioma, astrocytoma, brainstem glioma, ependymoma, aligodendrogliorna, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; (12) breast cancer,including, but not limited to, adenocarcinoma, lobular (small cell)carcinoma, intraductal carcinoma, medullary breast cancer, mutinousbreast cancer, tubular breast cancer, papillary breast cancer, primarycancers, Paget's disease, and inflammatory breast cancer; (13) adrenalcancer, including, but not limited to, pheochromocytom andadrenocortical carcinoma; (14) thyroid cancer, including, but notlimited to, papillary or follicular thyroid cancer, medullary thyroidcancer, and anaplastic thyroid cancer; (15) pancreatic cancer,including, but not limited to, insulinoma, gastrinoma, glucagonoma,vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor;(16) pituitary cancer, including, but limited to, Cushing's disease,prol actin-secreting tumor, acromegaly, and diabetes insipius; (17) eyecancer, including, but not limited, to ocular melanoma such as irismelanoma, choroidal melanoma, and cilliary body melanoma, andretinoblastoma; (18) vaginal cancer, including, but not limited to,squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvarcancer, including, but not limited to, squamous cell carcinoma,melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget'sdisease; (20) cervical cancers, including, but not limited to, squamouscell carcinoma, and adenocarcinoma; (21) uterine cancer, including, butnot limited to, endometrial carcinoma and uterine sarcoma; (22) ovariancancer, including, but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; (23) esophagealcancer, including, but not limited to, squamous cancer, adenocarcinoma,adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamouscarcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oatcell (small cell) carcinoma; (24) stomach cancer, including, but notlimited to, adenocarcinoma, fungating (polypoid), ulcerating,superficial spreading, diffusely spreading, malignant lymphoma,liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26)rectal cancer; (27) liver cancer, including, but not limited to,hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer,including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas,including, but not limited to, pappillary, nodular, and diffuse; (30)lung cancer, including, but not limited to, non-small cell lung cancer,squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma,large-cell carcinoma, and small-cell lung cancer; (31) testicularcancer, including, but not limited to, germinal tumor, seminoma,anaplastic, classic (typical), spermatocytic, nonserninoma, embryonalcarcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor);(32) prostate cancer, including, but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oralcancer, including, but not limited to, squamous cell carcinoma; (35)basal cancer; (36) salivary gland cancer, including, but not limited to,adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma;(37) pharynx cancer, including, but not limited to, squamous cell cancerand verrucous; (38) skin cancer, including, but not limited to, basalcell carcinoma, squamous cell carcinoma and melanoma, superficialspreading melanoma, nodular melanoma, lentigo malignant melanoma, andacral lentiginous melanoma; (39) kidney cancer, including, but notlimited to, renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer);(40) Wilms' tumor; (41) bladder cancer, including, but not limited to,transitional cell carcinoma, squamous cell cancer, adenocarcinoma, andcarcinosarcoma; (42) reproductive cancers, such as cervical cancer,uterus cancer, ovarian cancer, or testicular cancer; (43) esophaguscancer; (44) laryngeal cancer; (45) head and neck cancer (such as mouth,nose, throat, larynx, sinuses, or salivary glands cancer); and othercancer, including, not limited to, myxosarcoma, osteogenic sarcoma,endotheliosarcoma, lymphangio-endotheliosarcoma, mesothelioma,synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,bronchogenic carcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, and papillary adenocarcinomas (SeeFishman et al., 1985, Medicine, 2d Ed., J. B. Lippincott Co.,Philadelphia and Murphy et al., 1997, Informed Decisions: The CompleteBook of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin,Penguin Books U.S.A., Inc., United States of America). In someembodiments, the cancer is non-small cell lung cancer, melanoma, renalcell cancer, head and neck cancer, colon cancer, or mesothelioma. Insome embodiments, the cancer is non-small cell lung cancer. In someembodiments, the cancer is melanoma.

In certain embodiments, provided herein are methods of treatinghematological malignancy with a combination of an effective amount of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand an effective amount of CD20 inhibitor in a patient. In certainembodiments, the hematological malignancy is a leukemia, a lymphoma, amyeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, T-cellmalignancy, or a B-cell malignancy. In some embodiments, thehematological malignancy is Hodgkin's lymphoma.

In certain embodiments, the hematological malignancy is a T-cellmalignancy. In certain embodiments, T-cell malignancies includeperipheral T-cell lymphoma not otherwise specified (PTCL-NOS),anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneousT-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-celllymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-deltaT-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, ortreatment-related T-cell lymphomas.

In certain embodiments, the hematological malignancy is a B-cellmalignancy. In some embodiments, the synergistic combination a PI3Kinhibitor described herein and a CD20 inhibitor is used in the treatmentof B cell malignancies. In certain embodiments, B cell malignanciesinclude acute lymphoblastic leukemia (ALL), acute myelogenous leukemia(AML), chronic myelogenous leukemia (CML), acute monocytic leukemia(AMoL), chronic lymphocytic leukemia (CLL), high-risk chroniclymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risksmall lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuselarge B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom'smacroglobulinemia, multiple myeloma, extranodal marginal zone B celllymphoma, nodal marginal zone B cell lymphoma, Burkitts lymphoma,non-Burkitt high grade B cell lymphoma, primary mediastinal B-celllymphoma (PMBL), immunoblastic large cell lymphoma, precursorB-lymphoblastic lymphoma, B cell prolymphocytic leukemia,lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cellmyeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma,intravascular large B cell lymphoma, primary effusion lymphoma, orlymphomatoid granulomatosis. In certain embodiments, the B cellmalignancy is selected from non-Hodgkin's lymphoma, Burkitt's lymphoma,small lymphocytic lymphoma, primary effusion lymphoma, diffuse largeB-cell lymphoma, splenic marginal zone lymphoma, MALT (mucosa-associatedlymphoid tissue) lymphoma, hairy cell leukemia, chronic lymphocyticleukemia, B-cell prolymphocytic leukemia, B cell lymphomas (e.g. variousforms of Hodgkin's disease, B cell non-Hodgkin's lymphoma (NHL),leukemias (e.g. acute lymphoblastic leukemia (ALL), chronic lymphocyticleukemia (CLL; also termed B cell chronic lymphocytic leukemia BCLL),hairy cell leukemia and chronic myoblastic leukemia) and myelomas (e.g.multiple myeloma). In certain embodiments, the B-cell malignancy isdiffuse large B-cell lymphoma (DLBCL). In certain embodiments, thehematological malignancy is diffuse large B-cell lymphoma (DLBCL). Incertain embodiments, the DLBCL is an activated B-cell DLBCL (ABC-DLBCL),a germinal center B-cell like DLBCL (GBC-DLBCL), a double hit DLBCL(DH-DLBCL), or a triple hit DLBCL (TH-DLBCL). In some embodiments, thehematological malignancy is B-cell non-Hodgkin's lymphoma (NHL). In someembodiments, the hematological malignancy is B-cell indolentnon-Hodgkin's lymphoma (NHL). In certain embodiments, the B-cellmalignancy is selected from chronic lymphocytic leukemia (CLL), smalllymphocytic lymphoma (SLL), follicular lymphoma (FL), marginal zone Bcell lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), and highgrade non-Hodgkin's lymphoma. In certain embodiments, the B-cellmalignancy is selected from chronic lymphocytic leukemia (CLL),follicular lymphoma (FL), marginal zone B cell lymphoma (MZL), ordiffuse large B-cell lymphoma (DLBCL).

In certain embodiments, the hematological malignancy is a relapsed orrefractory hematological malignancy. In certain embodiments, therelapsed or refractory hematological malignancy is a relapsed orrefractory T-cell malignancy. In certain embodiments, the relapsed orrefractory hematological malignancy is a relapsed or refractory B-cellmalignancy. In some embodiments, the cancer is relapsed B-cellnon-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Insome embodiments, the hematological malignancy is relapsed B-cellnon-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL).

Dosages and Dosing Regimens

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration as described elsewhere herein.

In certain embodiments, the methods provided herein compriseadministering a compound of Formula (I), or an isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof and a CD20 inhibitor to a patient simultaneously or sequentiallyby the same or different routes of administration.

The suitability of a particular route of administration employed for aparticular active agent will depend on the active agent itself (e.g.,whether it can be administered orally without decomposing prior toentering the blood stream) and the disease being treated.

In certain embodiments, the compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and a CD20 inhibitor is administeredsimultaneously, at essentially the same time, or sequentially. Ifadministration takes place sequentially, the CD20 inhibitor may beadministered before or after administration of a compound of

Formula (I), or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In someembodiments, the CD20 inhibitor is administered before administration ofa compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In some embodiments, the CD20 inhibitor is administered simultaneouslywith administration of a compound of Formula (I), an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In some embodiments, the CD20 inhibitor is administeredafter the administration of a compound of Formula (I), an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

A compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand the CD20 inhibitor need not be administered by means of the samevehicle. In some embodiments, the CD20 inhibitor and a compound ofFormula (I), or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof are administeredin different vehicles. The CD20 inhibitor may be administered one ormore times, and the number of administrations of each component of thecombination may be the same or different. In addition, a compound ofFormula (I), or an isotopic variant thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof and the CD20inhibitor need not be administered at the same site.

In some instances, the methods described herein further compriseadministering the PI3K inhibitor in combination with CD20 inhibitor tothe subject or patient in need thereof in multiple cycles repeated on aregular schedule with periods of rest in between each cycle. Forexample, in some instances, treatment is given for one week followed bythree weeks of rest is one treatment cycle.

In some instances, a cycle comprises administration of the PI3Kinhibitor at the same time as administration of the CD20 inhibitor. Insome instances, the PI3K inhibitor and the CD20 inhibitor areadministered for about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 8 days, about 9 days,about 10 days, about 11 days, about 12 days, about 13 days, about 14days, about 15 days, about 16 days, about 17 days, about 18 days, about19 days, about 20 days, about 21 days, about 22 days, about 23 days,about 24 days, about 25 days, about 26 days, about 27 days, or about 28days.

In some instances, a cycle comprises administration of the PI3Kinhibitor first followed by administration of the CD20 inhibitor second.In some instances, the PI3K inhibitor is administered for about 1 day,about 2 days, about 3 days, about 4 days, about 5 days, about 6 days,about 7 days, about 8 days, about 9 days, about 10 days, about 11 days,about 12 days, about 13 days, or about 14 days followed byadministration of the CD20 inhibitor for about 1 day, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, about 7 days,about 8 days, about 9 days, about 10 days, about 11 days, about 12 days,about 13 days, or about 14 days.

In some instances, a cycle comprises administration of the PI3Kinhibitor first followed by concurrent administration of the CD20inhibitor. In some instances, the PI3K inhibitor is first administeredfor about 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, about 12 days, about 13 days, or about 14 days followedby the concurrent administration of the CD20 inhibitor for about 1 day,about 2 days, about 3 days, about 4 days, about 5 days, about 6 days,about 7 days, about 8 days, about 9 days, about 10 days, about 11 days,about 12 days, about 13 days, or about 14 days. In some instances, thePI3K inhibitor is first administered for about 1 day, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, or about 7 daysfollowed by the concurrent administration of the CD20 inhibitor forabout 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, about 12 days, about 13 days, or about 14 days. In someinstances, the PI3K inhibitor is first administered for about 7 daysfollowed by the concurrent administration of the CD20 inhibitor forabout 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, about 12 days, about 13 days, or about 14 days. In someinstances, the PI3K inhibitor is first administered for about 7 daysfollowed by the concurrent administration of the CD20 inhibitor forabout 10 days, about 11 days, about 12 days, about 13 days, or about 14days.

In some instances, a cycle comprises administration of the PI3Kinhibitor only. In some instances, the PI3K inhibitor is administeredfor about 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, about 12 days, about 13 days, about 14 days, about 15days, about 16 days, about 17 days, about 18 days, about 19 days, about20 days, about 21 days, about 22 days, about 23 days, about 24 days,about 25 days, about 26 days, about 27 days, or about 28 days.

In some instances, a cycle comprises administration of the the CD20inhibitor only. In some instances, the CD20 inhibitor is administeredfor about 1 day, about 2 days, about 3 days, about 4 days, about 5 days,about 6 days, about 7 days, about 8 days, about 9 days, about 10 days,about 11 days, about 12 days, about 13 days, about 14 days, about 15days, about 16 days, about 17 days, about 18 days, about 19 days, about20 days, about 21 days, about 22 days, about 23 days, about 24 days,about 25 days, about 26 days, about 27 days, or about 28 days.

In some instances, the method for multiple cycle chemotherapy comprisesthe administration of a second cycle within about 60 days or about 3months. In some instances, the method for multiple cycle chemotherapycomprises the administration of a second cycle within 50 days. Inanother instance, the second cycle is administered within 45, 40, 35,30, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 day(s) of thefirst cycle. In some embodiments, the administration of any additionalcycles is within 50 days of the previous cycle. In some embodiments, theadministration of any additional cycles is within 10 days of theprevious cycle. In some embodiments, the administration of anyadditional cycles is within 9 days of the previous cycle. In someembodiments, the administration of any additional cycles is within 8days of the previous cycle. In some embodiments, the administration ofany additional cycles is within 7 days of the previous cycle. In someembodiments, the administration of any additional cycles is within 6days of the previous cycle. In some embodiments, the administration ofany additional cycles is within 5 days of the previous cycle. In someembodiments, the administration of any additional cycles is within 4days of the previous cycle. In some embodiments, the administration ofany additional cycles is within 3 days of the previous cycle. In someembodiments, the administration of any additional cycles is within 2days of the previous cycle. In some embodiments, the administration ofany additional cycles is within 1 day of the previous cycle. In anotherembodiment, the additional cycle is administered within 45, 40, 35, 30,25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 days of theprevious cycle.

The length of a treatment cycle depends on the treatment being given. Insome embodiments, the length of a treatment cycle ranges from two to sixweeks. In some embodiments, the length of a treatment cycle ranges fromfour to six weeks. In some embodiments, the length of a treatment cycleis 28 days. In some embodiments, the length of a treatment cycle is 56days. In some embodiments, a treatment cycle lasts one, two, three, orfour weeks. In some embodiments, a treatment cycle lasts four weeks. Thenumber of treatment doses scheduled within each cycle also variesdepending on the drugs being given.

In certain instances, the compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof, is administered to the subject on a 28-daycycle. In some embodiments, the compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof, is administered to the subject for at leastone 28-day cycle. In some embodiments, the compound of Formula (I), oran enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof, is administeredto the subject for at least two 28-day cycles.

In certain embodiments, the compound of Formula (I), or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof, is administered to the subject fora period of up to about 7 days. In some embodiments, the days over whichthe compound of Formula (I), or an enantiomer, a mixture of enantiomers,a mixture of two or more diastereomers, or an isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof are intermittent. In some embodiments, administering to subjectthe compound of Formula (I), or an enantiomer, a mixture of enantiomers,a mixture of two or more diastereomers, or an isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof for about 7 consecutive days in a 28-day cycle.

In some embodiments, the method comprises an intermittent dosingschedule (IS), comprising administering to subject the compound ofFormula (I), or an enantiomer, a mixture of enantiomers, a mixture oftwo or more diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofonce daily for 7 consecutive days followed by 21 days without treatmentin a 28-day cycle. In some embodiments, the compound of Formula (I), oran enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof, is administeredto the subject for at least one 28-day cycle. In some embodiments, theIS avoids or reduces adverse or unwanted side effects associated withthe use of the PI3K inhibitor, such as enterocolitis (manifested asdiarrhea), cutaneous toxicities, liver toxicity (manifested as elevationof transaminases), pulmonary toxicity (manifested as non-infectiouspneumonitis), and infections. In some embodiments, the IS avoids orreduces enterocolitis, rash, transaminitis, or combinations thereof.

In some embodiments, the method comprises a continuous daily dosingschedule (CS), comprising administering to subject the compound ofFormula (I), or an enantiomer, a mixture of enantiomers, a mixture oftwo or more diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofonce daily for 28 consecutive days in a 28-day cycle. In someembodiments, the compound of Formula (I), or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, or an isotopicvariant thereof, or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof, is administered to the subject for at leasttwo CS 28-day cycles. In certain instances, the method comprises acontinuous daily dosing schedule (CS) for at least two CS 28-day cycles,followed by an intermittant dosing schedule (IS), comprisingadministering to subject the compound of Formula (I), or an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof once daily for 7 consecutive daysfollowed by 21 days without treatment in a 28-day cycle after the atleast two CS 28-day cycles. In some embodiments, the dosing scheduleavoids or reduces adverse or unwanted side effects associated with theuse of the PI3K inhibitor, such as enterocolitis (manifested asdiarrhea), cutaneous toxicities, liver toxicity (manifested as elevationof transaminases), pulmonary toxicity (manifested as non-infectiouspneumonitis), and infections. In some embodiments, the dosing scheduleavoids or reduces enterocolitis, rash, transaminitis, or combinationsthereof.

In some instances, the method for the administration of multiplecompounds comprises administering compounds within 48 hours or less ofeach other. In some embodiments administration occurs within 24 hours,12 hours, 6 hours, 3 hours, 1 hour, or 15 minutes. In some instances,the compounds are administered simultaneously. One example ofsimultaneous administration is the injection of one compound immediatelybefore, after, or during the oral administration of the second compound,immediately referring to a time less than about 5 minutes.

In some instances, the method for the administration of multiplecompounds occurs in a sequential order, wherein the PI3K inhibitor isadministered before the CD20 inhibitor. In another instance, the CD20inhibitor is administered before the PI3K inhibitor.

In some instances, the method for administering the PI3K inhibitor isoral and the method for administering the CD20 inhibitor is byinjection. In some instances, the method for administering the PI3Kinhibitor is by inhalation and the method for administering the CD20inhibitor is by injection. In some instances, the method foradministering the PI3K inhibitor is by injection and the method foradministering the CD20 inhibitor is by injection.

In certain embodiments, a compound of Formula (I), or an isotopicvariant thereof, or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and a CD20 inhibitor is cyclicallyadministered to a patient. As discussed above, cycling therapy involvesthe administration of an active agent or a combination of active agentsfor a period of time, followed by a rest for a period of time, andrepeating this sequential administration. In some embodiments, cyclingtherapy reduces the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improves the efficacy of the treatment.

In some embodiments, the compound of Formula (I) is administered daily,every other day, every other day 3 times a week, every 2 weeks, every 3weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5days, every 6 days, weekly, bi-weekly, 3 times a week, 4 times a week, 5times a week, 6 times a week, once a month, twice a month, 3 times amonth, once every 2 months, once every 3 months, once every 4 months,once every 5 months, or once every 6 months. In some embodiments, thecompound of Formula (I) is administered daily. In some embodiments, thecompound of Formula (I) is administered daily for a period of up toabout 28 days. In some embodiments, the compound of Formula (I) isadministered daily for a period of up to about 7 days.

In some embodiments, the CD20 inhibitor is administered daily, everyother day, every other day 3 times a week, every 3 days, every 4 days,every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, every4 weeks, every 5 weeks, bi-weekly, 3 times a week, 4 times a week, 5times a week, 6 times a week, once a month, twice a month, 3 times amonth, once every 2 months, once every 3 months, once every 4 months,once every 5 months, or once every 6 months. In some embodiments, theCD20 inhibitor is administered 8 times in 6 months.

In some instances, the compound of Formula (I) or the CD20 inhibitor isoptionally given continuously; alternatively, the dose of drug beingadministered is temporarily reduced or temporarily suspended for acertain length of time (i.e., a “drug holiday”). In some embodiments,the length of the drug holiday varies between 2 days and 1 year,including by way of example only, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 8 days, 9 days, 10 days, 12 days, 14 days, 15 days, 20days, 21 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days,150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days,350 days, or 365 days. The dose reduction during a drug holiday includesfrom 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or100%.

In certain embodiments, in the treatment, prevention, or amelioration ofone or more symptoms of the disorders, diseases, or conditions describedherein, an appropriate dosage level of a compound of Formula (I), or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof generally is ranging from about 1to 1000 mg, from about 1 to about 500 mg, from about 5 to about 500 mg,from about 5 to about 200 mg, from about 5 to about 250 mg or from about10 to about 150 mg which can be administered in single or multipledoses. In certain embodiments, the compound of Formula (I), or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof is administered in an amount ofabout 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155,160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325,350, 375, 400, 450 or 500 mg. In certain embodiments, the compound ofFormula (I), or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof is administered inan amount of about 60 mg, about 120 mg, about 150 mg, or about 180 mg.In certain embodiments, the compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof is administered in an amount of about 60 mg.In certain embodiments, the compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof is administered in an amount of about 1,about 5, about 10, about 15, about 20, about 25, about 30, about 35,about 40, about 45, about 50, about 55, about 60, about 65, about 70,about 75, about 80, about 85, about 90, about 95, about 100, about 105,about 110, about 115, about 120, about 125, about 130, about 135, about140, about 145, about 150, about 155, about 160, about 165, about 170,about 175, about 180, about 185, about 190, about 195, about 200, about225, about 250, about 275, about 300, about 325, about 350, about 375,about 400, about 450, or about 500 mg/day. In certain embodiments, thecompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered in an amount of about 45 mg/day. In certain embodiments,the compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered in an amount of about 60 mg/day. In certain embodiments,the compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered in an amount of about 90 mg/day. In certain embodiments,the compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered in an amount of about 120 mg/day. In certainembodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 150 mg/day. Incertain embodiments, the compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered in an amount of about 180 mg/day.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets containing from about 1.0 toabout 1,000 mg of a compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof, in one embodiment, about 1, about 5, about 10, about15, about 20, about 25, about 50, about 75, about 100, about 150, about200, about 250, about 300, about 400, about 500, about 600, about 750,about 800, about 900, and about 1,000 mg of the a compound of Formula(I), or an isotopic variant thereof; or a pharmaceutically acceptablesalt, solvate, hydrate, or prodrug thereof for the symptomaticadjustment of the dosage to the patient to be treated.

In some embodiments, the pharmaceutical compositions provided herein canbe formulated in the form of tablets containing about 45 mg of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.The pharmaceutical compositions can be administered on a regimen of 1 to4 times per day, including once, twice, three times, and four times perday. In certain embodiments, a compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof is administered to a patient in need thereofin an amount of about 45 mg daily for 28 days or 56 days. In certainspecific embodiments, a compound of Formula (I), or an isotopic variantthereof, or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered to a patient in need thereof in anamount of about 45 mg daily for 28 days. In other specific embodiments,a compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered to a patient in need thereof in an amount of about 45 mgdaily for 56 days.

In some embodiments, the pharmaceutical compositions provided herein canbe formulated in the form of tablets containing about 60 mg of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.The pharmaceutical compositions can be administered on a regimen of 1 to4 times per day, including once, twice, three times, and four times perday. In certain embodiments, a compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof is administered to a patient in need thereofin an amount of about 60 mg daily for 28 days or 56 days. In certainspecific embodiments, a compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered to a patient in need thereof in anamount of about 60 mg daily for 28 days. In other specific embodiments,a compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered to a patient in need thereof in an amount of about 60 mgdaily for 56 days.

In some embodiments, the pharmaceutical compositions provided herein canbe formulated in the form of tablets containing about 90 mg of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.The pharmaceutical compositions can be administered on a regimen of 1 to4 times per day, including once, twice, three times, and four times perday. In certain embodiments, a compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof is administered to a patient in need thereofin an amount of about 90 mg daily for 28 days or 56 days. In certainspecific embodiments, a compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered to a patient in need thereof in anamount of about 90 mg daily for 28 days. In other specific embodiments,a compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered to a patient in need thereof in an amount of about 90 mgdaily for 56 days.

In some embodiments, the pharmaceutical compositions provided herein canbe formulated in the form of tablets containing about 120 mg of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.The pharmaceutical compositions can be administered on a regimen of 1 to4 times per day, including once, twice, three times, and four times perday. In certain embodiments, a compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof is administered to a patient in need thereofin an amount of about 120 mg daily for 28 days or 56 days. In certainspecific embodiments, a compound of Formula (I), or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered to a patient in need thereof in anamount of about 120 mg daily for 28 days. In other specific embodiments,a compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered to a patient in need thereof in an amount of about 120mg daily for 56 days.

In some embodiments, the pharmaceutical compositions provided herein canbe formulated in the form of tablets containing about 150 mg of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.The pharmaceutical compositions can be administered on a regimen of 1 to4 times per day, including once, twice, three times, and four times perday. In certain embodiments, a compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof is administered to a patient in need thereofin an amount of about 150 mg daily for 28 days or 56 days. In certainspecific embodiments, a compound of Formula (I), or an isotopic variantthereof, or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered to a patient in need thereof in anamount of about 150 mg daily for 28 days. In other specific embodiments,a compound of Formula (I), or an isotopic variant thereof, or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered to a patient in need thereof in an amount of about 150mg daily for 56 days.

In some embodiments, the pharmaceutical compositions provided herein canbe formulated in the form of tablets containing about 180 mg of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.The pharmaceutical compositions can be administered on a regimen of 1 to4 times per day, including once, twice, three times, and four times perday. In certain embodiments, a compound of Formula (I), or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof is administered to a patient in need thereofin an amount of about 180 mg daily for 28 days or 56 days. In certainspecific embodiments, a compound of Formula (I), or an isotopic variantthereof, or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof is administered to a patient in need thereof in anamount of about 180 mg daily for 28 days. In other specific embodiments,a compound of Formula (I), or an isotopic variant thereof, or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofis administered to a patient in need thereof in an amount of about 180mg daily for 56 days.

In certain embodiments, the CD20 inhibitor used in combination with acompound of Formula (I), or an isotopic variant thereof, or apharmaceutically acceptable salt, solvate, hydrate, or prodrug, isrituximab. In certain embodiments, the methods described herein furthercomprise administering rituximab as an intravenous infusion in 28 dayscycles. In certain embodiments, rituximab is administered as anintravenous infusion for multiple 28 days cycles. In certainembodiments, rituximab is administered as an intravenous infusion at adose of 375 mg/m² in the first cycle and 500 mg/m² in cycles 2-6. Incertain embodiments, rituximab is administered intravenously as aninfusion at a dose of 375 mg/m² per cycle. In certain embodiments,rituximab is administered as an intravenous infusion at a dose of 375mg/m² for a total of 8 doses in 6 months.

In certain embodiments, the CD20 inhibitor used in combination with acompound of Formula (I), or an isotopic variant thereof, or apharmaceutically acceptable salt, solvate, hydrate, or prodrug, isofatumumab. In certain embodiments, the methods described herein furthercomprise administering ofatumumab as an intravenous infusion every week.In certain embodiments, ofatumumab is administered as an intravenousinfusion for multiple cycles. In certain embodiments, ofatumumab isadministered as an intravenous infusion at a dose of 300 mg initialdose, followed 1 week later by 2,000 mg weekly for 7 doses, followed 4weeks later by 2,000 mg every 4 weeks for 4 doses.

In certain embodiments, the CD20 inhibitor used in combination with acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug, isobinutuzumab. In certain embodiments, the methods described hereinfurther comprise administering obinutuzumab as an intravenous infusionin 28 days cycles. In certain embodiments, obinutuzumab is administeredas an intravenous infusion for multiple cycles 28 days cycles. Incertain embodiments, obinutuzumab is administered as an intravenousinfusion at a dose of 100 mg on day 1 and 900 mg on day 2 Cycle 1, 1000mg on day 8 and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2-6. Incertain embodiments, obinutuzumab is administered as an intravenousinfusion at a dose of 1000 mg on day 1, 8 and 15 of Cycle 1, and 1000 mgon day 1 of Cycles 2-6, and then every 2 months for 2 years.

In certain embodiments, the CD20 inhibitor used in combination with acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug, isocaratuzumab. In certain embodiments, the methods described hereinfurther comprise administering ocaratuzumab as a subcutaneous injectionevery week. In certain embodiments, ocaratuzumab is administered as asubcutaneous injection for multiple cycles. In certain embodiments,ocaratuzumab is administered at a dose between about 20 mg to about 100mg per week. In certain embodiments, ocaratuzumab is administered at adose of about 40 mg per week. In certain embodiments, ocaratuzumab isadministered at a dose of about 80 mg per week.

In certain embodiments, the CD20 inhibitor used in combination with acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug, isocrelizumab. In certain embodiments, the methods described hereinfurther comprise administering ocrelizumab as an intravenous infusion in24 weeks cycles. In certain embodiments, ocrelizumab is administered asan intravenous infusion for multiple cycles. In certain embodiments,ocrelizumab is administered as an intravenous infusion at a dose of 600mg as a 300 mg infusions on days 1 and 15 for the first dose and as asingle infusion of 600 mg for all subsequent infusions every 24 weeks.

In certain embodiments, the CD20 inhibitor used in combination with acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug, isublituximab. In certain embodiments, the methods described hereinfurther comprise administering ublituximab as an intravenous infusion incycles. In certain embodiments, ublituximab is administered as anintravenous infusion for multiple cycles. In certain embodiments,ublituximab is administered as an intravenous infusion at day 1, day 8and day 15 of every cycle.

In certain embodiments, the CD20 inhibitor used in combination with acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug, isBTCT4465A. In certain embodiments, the methods described herein furthercomprise administering BTCT4465A as an intravenous infusion in 21 dayscycles. In certain embodiments, BTCT4465A is administered as anintravenous infusion for multiple cycles. In certain embodiments,BTCT4465A is administered as an intravenous infusion on Day 1 of each21-day cycle. In certain embodiments, BTCT4465A is administered as anintravenous infusion on Days 1, 8, and 15 of Cycle 1 and thereafter onDay 1 of each 21-day cycle.

In certain embodiments, the CD20 inhibitor used in combination with acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug, isveltuzumab. In certain embodiments, the methods described herein furthercomprise administering veltuzumab as an intravenous infusion or asubcutaneous injection in weekly cycles. In certain embodiments,veltuzumab is administered as an intravenous infusion or a subcutaneousinjection for multiple weekly cycles. In certain embodiments, veltuzumabis administered as an intravenous infusion or a subcutaneous injectionat a dose of 80 mg/m² once weekly for 4 weeks. In certain embodiments,veltuzumab is administered as an intravenous infusion or a subcutaneousinjection at a dose of 120 mg/m² once weekly for 4 weeks. In certainembodiments, veltuzumab is administered as an intravenous infusion or asubcutaneous injection at a dose of 200 mg/m² once weekly for 4 weeks.In certain embodiments, veltuzumab is administered as an intravenousinfusion or a subcutaneous injection at a dose of 375 mg/m² once weeklyfor 4 weeks.

In certain embodiments, the CD20 inhibitor used in combination with acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug, isTRU-015. In certain embodiments, the methods described herein furthercomprise administering TRU-015 as an intravenous infusion in weeklycycles. In certain embodiments, TRU-015 is administered as anintravenous infusion for multiple weekly cycles. In certain embodiments,TRU-015 is administered at a dose between about 100 mg to about 1200 mgper week. In certain embodiments, TRU-015 is administered at a dose ofabout 400 mg per week. In certain embodiments, TRU-015 is administeredat a dose of about 700 mg per week. In certain embodiments, TRU-015 isadministered at a dose of about 1000 mg per week.

In certain embodiments, a CD20 inhibitor is administered once per day,twice per day, or three times per day. In certain embodiments, the CD20inhibitor is administered once per day. In certain embodiments, the CD20inhibitor is administered once per day, twice per day, or three timesper day. In certain embodiments, the CD20 inhibitor is administered onceper day. In certain embodiments, the CD20 inhibitor is co-administered(e.g., in a single dosage form), once per day.

In certain embodiments, the CD20 inhibitor is administered weekly. Incertain embodiments, the CD20 inhibitor is administered once every two,three, four, or five weeks. In certain embodiments, the CD20 inhibitoris administered once every four weeks. In certain embodiments, the CD20inhibitor is administered is 21 days cycles. In certain embodiments, theCD20 inhibitor is administered is 28 days cycles. In certainembodiments, the CD20 inhibitor is administered intravenously. Incertain embodiments, the CD20 inhibitor is administered as anintravenous infusion. In certain embodiments, the CD20 inhibitor isadministered subcutaneously.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Additional Combination Therapy

In certain embodiments, the methods of combination therapy comprising acompound of Formula (I), an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand a CD20 inhibitor can also be combined or used in combination with athird agent or therapies useful in the treatment, prevention, oramelioration of one or more symptoms of a proliferative disorders,diseases, or conditions.

Suitable third agent of therapies include, but are not limited to, (1)alpha-adrenergic agents; (2) antiarrhythmic agents; (3)anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics,such as anthracyclines, bleomycins, mitomycin, dactinomycin, andplicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylatingagents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas,ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol,argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione,warfarin, and xirnelagatran, (7) anti-diabetic agents, such asbiguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose),insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g.,glimepiride, glyburide, and glipizide), thiozolidinediones (e.g.,troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma monists;(8) antifungal agents, such as amorolfine, amphotericin B,anidulafungin, bifonazole, butenafine, butoconazole, caspofungin,ciclopirox, clotrimazole, econazole, fenticonazole, filipin,fluconazole, isoconazole, itraconazole, ketoconazole, micafungin,miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole,posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine,terconazole, tioconazole, and voriconazole; (9) antiinflammatories,e.g., non-steroidal anti-inflammatory agents, such as aceclofenac,acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac,carprofen, celecoxib, choline magnesium salicylate, diclofenac,diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen,flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam,loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam,metamizole, methyl salicylate, magnesium salicylate, nabumetone,naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone,piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen,tenoxicam, tiaprofenic acid, and tolmetin; (10) antimetabolites, such asfolate antagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid secjuestrants, such as questran; (17) calcium channelblockers, such as amlodipine besylate; (18) chemotherapeutic agents;(19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib androfecoxib; (20) cyclosporins; (21) cytotoxic drugs, such as azathioprineand cyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) famesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37) niacin; (38)phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); (39) plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF)antagonists; (41) platinum coordination complexes, such as cisplatin,satraplatin, and carboplatin; (42) potassium channel openers; (43)prenyl-protein transferase inhibitors; (44) protein tyrosine kinaseinhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors;(47) steroids, such as aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombininhibitors, such as hirudin; (50) thrombolytic agents, such asanistreplase, reteplase, tenecteplase, tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC); (51)thromboxane receptor antagonists, such as ifetroban; (52) topoisomeraseinhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors),such as omapatrilat and gemopatrilat, and (54) other miscellaneousagents, such as, hydroxyurea, procarbazine, mitotane,hexamethylmelamine, and gold compounds.

In certain embodiments, the third therapies that may be used incombination with the methods provided herein include, but are notlimited to, surgery, endocrine therapy, biologic response modifiers(e.g., interferons, interleukins, and tumor necrosis factor (TNF)),hyperthermia and cryotherapy, and agents to attenuate any adverseeffects (e.g., antiemetics).

In certain embodiments, the third therapeutic agents that may be used incombination with the compounds provided herein include, but are notlimited to, alkylating drugs (mechlorethamine, chlorambucil,cyclophosphamide, melphalan, and ifosfamide), antimetabolites(cytarabine (also known as cytosine arabinoside or Ara-C), andmethotrexate), purine antagonists and pyrimidine antagonists(6-mercaptopurine, 5-fluorouracil, cytarbine, and gemcitabine), spindlepoisons (vinblastine, vincristine, and vinorelbine), podophyllotoxins(etoposide, irinotecan, and topotecan), antibiotics (daunorubicin,doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine andlomustine), enzymes (asparaginasc), and hormones (tamoxifen, leuprolide,flutamide, and megestrol), imatinib, adriamycin, dexamethasone, andcyclophosphamide.

In another embodiment, the method provided herein comprisesadministration of a compound of Formula (I), or an isotopic variantthereof, or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof and a CD20 inhibitor, together with administering one ormore chemotherapeutic agents and/or therapies selected from: alkylationagents (e.g., cisplatin, carboplatin); antimetabolites (e.g.,methotrexate and 5-FU); antitumor antibiotics (e.g., adriamymycin andbleomycin); antitumour vegetable alkaloids (e.g., taxol and etoposide);antitumor hormones (e.g., dexamethasone and tamoxifen); antitumourimmunological agents (e.g., interferon α, β, and γ); radiation therapy;and surgery. In certain embodiments, the one or more chemotherapeuticagents and/or therapies are administered to the subject before, during,or after the administration of a compound of Formula (I), or an isotopicvariant thereof, or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof and a CD20 inhibitor.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand a CD20 inhibitor. When a compound of Formula (I) and a CD20inhibitor are used contemporaneously with one or more other drugs, apharmaceutical composition containing such other drugs in addition tothe compound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand a CD20 inhibitor can be utilized, but is not required. Accordingly,the pharmaceutical compositions provided herein include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to a compound of Formula (I).

Pharmaceutical Compositions and Routes of Administration

Provided herein is a pharmaceutical composition comprising a compound ofFormula (I), a CD20 inhibitor and a pharmaceutically acceptableexcipient, adjuvant, carrier, buffer, or stabilizer. In someembodiments, the compound of Formula (I) and a CD20 inhibitor arepresent in the same pharmaceutical composition. In some embodiments, thecompound of Formula (I) and the CD20 inhibitor are in differentpharmaceutical compositions.

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, and one or more pharmaceutically acceptable excipients orcarriers. The pharmaceutical compositions provided herein that areformulated for oral administration may be in tablet, capsule, powder, orliquid form. In some embodiments, a tablet comprises a solid carrier oran adjuvant. Liquid pharmaceutical compositions generally comprise aliquid carrier such as water, petroleum, animal or vegetable oils,mineral oil, or synthetic oil. Physiological saline solution, dextroseor other saccharide solution, or glycols such as ethylene glycol,propylene glycol, or polyethylene glycol may be included. In someembodiments, a capsule comprises a solid carrier such as gelatin.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers. Where pharmaceutical compositions may be formulated forintravenous, cutaneous or subcutaneous injection, the active ingredientwill be in the form of a parenterally acceptable aqueous solution, whichis pyrogen-free and has a suitable pH, isotonicity, and stability. Thoseof relevant skill in the art are well able to prepare suitable solutionsusing, for example, isotonic vehicles, such as Sodium Chlorideinjection, Ringer's injection, or Lactated Ringer's injection. In someembodiments, preservatives, stabilizers, buffers, antioxidants, and/orother additives are included.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers.

The pharmaceutical compositions can also be formulated as modifiedrelease dosage forms, including delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, andprogrammed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Delivery Technology,2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, N.Y.,2008).

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

In certain embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more chemotherapeutic agents as defined herein.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate;

microcrystalline cellulose, such as sodium starch glycolate; polacrilinpotassium; starches, such as corn starch, potato starch, tapioca starch,and pre-gelatinized starch; clays; aligns; and mixtures thereof. Theamount of a disintegrant in the pharmaceutical compositions providedherein varies upon the type of formulation, and is readily discernibleto those of ordinary skill in the art. The amount of a disintegrant inthe pharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W. R. Grace Co., Baltimore, Md.) and CAB-0-SILO (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-0-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimetboxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimcthyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfate, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfate and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungi static concentrations. All parenteral formulations must besterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand metliacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, buty] rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

Articles of Manufacture

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes one or more containers and a dosage form of acompound of Formula (I), or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand a CD20 inhibitor.

In certain embodiments, the kit provided herein includes one or morecontainers and a dosage form of a compound of Formula (I), or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and CD20 inhibitor. Kits providedherein can further include devices that are used to administer theactive ingredients. Examples of such devices include, but are notlimited to, syringes, needle-less injectors drip bags, patches, andinhalers.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL, (microliters); M (molar); mM (millimolar), μM(micro molar); eq. (equivalent); mmol (millimoles), Hz (Hertz), MHz(megahertz); hr or hrs (hour or hours); min (minutes); and MS (massspectrometry).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Syntheses of Compounds I-XVI are described in U.S. Pat. No. 9,056,852B2, which is incorporated by reference for such disclosure.

Example 1 Study of a Combination of a PI3K Inhibitor and a CD20Inhibitor in Patients with Relapsed-Refractory CLL or Richter'sTransformation

The purpose of this study is to evaluate the safety and effectiveness ofCompound A35, A36, A68, or A70 (three does: 60 mg, 120 mg, and 150mg/day) and rituximab, in patients with advanced CLL or Richter'sTransformation.

Condition Intervention Phase Chronic Drug: Compound Phase 1/Phase 2Lymphocytic A35, A36, A68, Leukemia or A70 Biological: rituximab

-   Study Type: Interventional-   Study Design: Intervention Model: Single Group Assignment-   Masking: No masking-   Primary Purpose: Treatment

Primary Outcome Measures:

-   Determine Acceptable Adverse Events That Are Related to Treatment    [Time Frame: 6 months of therapy]. To determine the incidence of    adverse events, any potential abnormal laboratory results and any    dose-limiting toxicities

Secondary Outcome Measures:

-   Overall Response Rate [Time Frame: Up to 1 year]. The overall    response rate (ORR) in patients with CLL and Richter's    Transformation treated with a combination of Compound A35, A36, A68,    or A70 and rituximab.

Arms Assigned Interventions Experimental: Drug: rituximab + CompoundA35, A36, A68, Compound A35, A36, or A70 rituximab - 375 mg/m² in theA68, or A70 first cycle and 500 mg/m² in cycles A once daily oral agent2-6, administered every 28 days Biological: rituximab Compound A35, A36,A68, or A70 IV anti-CD20 oral daily dose - 60 mg monoclonal antibodyExperimental: Drug: rituximab + Compound A35, A36, A68, Compound A35,A36, or A70 rituximab - 375 mg/m² in the A68, or A70 first cycle and 500mg/m² in cycles A once daily oral agent 2-6, administered every 28 daysBiological: rituximab Compound A35, A36, A68, or A70 IV anti-CD20 oraldaily dose - 120 mg monoclonal antibody Experimental: Drug: rituximab +Compound A35, A36, A68, Compound A35, A36, or A70 rituximab - 375 mg/m²in the A68, or A70 first cycle and 500 mg/m² in cycles A once daily oralagent 2-6, administered every 28 days Biological: rituximab CompoundA35, A36, A68, or A70 IV anti-CD20 oral daily dose - 150 mg monoclonalantibodyEligibility

-   Ages Eligible for Study: 18 Years and older (Adult, Senior)-   Sexes Eligible for Study: All-   Accepts Healthy Volunteers: No    Criteria    Inclusion Criteria:-   Confirmed diagnosis of B-cell Chronic Lymphocytic Leukemia or    Richter's Transformation-   Refractory to or relapsed after at least 1 prior treatment regimen-   Eastern Cooperative Oncology Group (ECOG) score of 0 to 2    Exclusion Criteria:-   Any major surgery, chemotherapy or immunotherapy within the last 14    days-   Known hepatitis B virus, hepatitis C virus or HIV infection-   Active autoimmune disorder (with the exception of autoimmune    hemolytic anemia or ITP)

Example 2 Study of a Combination of a PI3K Inhibitor and a CD20Inhibitor in Patients with Relapsed B-Cell Non-Hodgkin's Lymphoma (NHL),Including Chronic Lymphocytic Leukemia (CLL)

The purpose of this study is to evaluate the safety and effectiveness ofCompound A35 (single dose: 60 mg/day) and rituximab, in patients withrelapsed B-cell malignancies.

Condition Intervention Phase Chronic Lymphocytic Leukemia (CLL) Drug:Compound Phase 1b Small Lymphocytic Lymphoma (SLL) A35 FollicularLymphoma (FL) Biological: Marginal Zone B Cell Lymphoma rituximab (MZL)Diffuse Large B-cell Lymphoma (DLBCL) High Grade Non-Hodgkin's Lymphoma

-   Study Type: Interventional-   Study Design: Intervention Model: Single Group Assignment-   Masking: No masking-   Primary Purpose: Treatment

Primary Outcome Measures:

-   Determine Acceptable Adverse Events That Are Related to Treatment    [Time Frame: 6 months of therapy]. To determine the incidence of    adverse events, any potential abnormal laboratory results and any    dose-limiting toxicities    Secondary Outcome Measures:-   Efficacy of Compound A35 with Rituximab as assessed by Overall    Response (OR) [Time Frame: 2 years]. The efficacy of Compound A35    with Rituximab will be determined by the overall response of    subjects calculated as the percent of subjects achieving a complete    remission (CR) or a complete remission with incomplete marrow    recovery (CRi) or a partial response (PR) according to the    International Workshop on Chronic Lymphocytic Leukemia (IWCLL).-   Evaluate the PK of Compound A35 with Rituximab (AUC) [Time Frame: 2    years] Determined by the Area Under the Concentration time curve    (AUC)-   Evaluate the PK of Compound A35 with Rituximab (Cmax) [Time Frame: 2    years] Determined by Peak Plasma Concentration (Cmax)

Arms Assigned Interventions Experimental: rituximab + Compound Drug:Compound A35 A35 rituximab - 375 mg/m², A once daily oral agentadministered for a total of 8 doses Biological: rituximab in 6 monthsCompound A35 oral daily IV anti-CD20 monoclonal dose - 60 mg antibodyEligibility

-   Ages Eligible for Study: 18 Years and older (Adult, Senior)-   Sexes Eligible for Study: All-   Accepts Healthy Volunteers: No    Criteria    Inclusion Criteria:-   Diagnosis of relapsed/refractory CLL SLL or FL, MZL, DLBCL and    high-grade B-cell lymphoma. Subjects must meet the following    criteria for relapsed or refractory disease:    -   Relapsed disease: a subject who previously achieved a CR or PR,        but demonstrated disease progression after a response duration        of >6 months    -   Refractory disease: a subject who demonstrated disease        progression within 6 months of most recent therapy-   No prior therapy with PI3K6 inhibitors-   No prior therapy with Bruton tyrosine kinase (BTK) inhibitors unless    the subject was intolerant of BTK therapy-   Subjects with CLL, SLL, FL, and MZL must have a failure of at least    1 prior systemic therapy and be considered by the investigator a    candidate for therapy with a rituximab-based regimen; subjects with    DLBCL and high-grade B-cell lymphoma must have a failure of at least    2 prior therapies.-   QT-interval corrected according to Fridericia's formula (QTcF) ≤450    milliseconds (ms)-   Left ventricular ejection fraction >50%-   For subjects, except those with CLL, must have at least one    bi-dimensionally measurable nodal lesion >1.5 cm, as defined by 2014    Lugano Classification (Cheson et al., J Clin Oncol 2014;    32(27):3059-68)-   Willingness to participate in collection of pharmacokinetic samples-   A negative serum pregnancy test within 14 days of study Day 0 for    females of childbearing potential    Exclusion Criteria:-   Known histological transformation from CLL to an aggressive lymphoma-   Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia-   Subjects who have tested positive for hepatitis B surface antigen    and/or hepatitis B core antibody-   Positive for hepatitis C virus antibody (HCV Ab) or human    immunodeficiency virus (HIV) antibody-   Ongoing drug-induced pneumonitis-   History of clinically significant cardiovascular abnormalities    Baseline Characterization

Fifteen patients were enrolled. The demographics and diseasecharacteristics are consistent with those of patients with relapsedB-cell NHL and CLL/SLL enrolled in other trials.

DLBCL/ FL MZL/CLL Total N = 9 N = 6 N = 15 Age in years, median 61(38-81) 71 (57-78) 62 (38-78) (range) Men, N (%) 7 (78%) 2 (33%) 9 (60%)Number of prior 3 (1-10) 2 (1-3) 2 (1-10) therapies, median (range)Subjects with prior 9 (100%) 5/5 (100%) * 14/14 (100%) anti-CD20therapy, N (%) Subjects with prior 9 (100%) 4/5 (80%) * 13/14 (93%)alkylating therapy, N (%) Subjects with lymph 3 (33%) 4/5 (80%) * 7/14(50%) nodes ≥5 cm, N (%) * Data not available in 1 patient with CLLrecently enrolled in the studyDosing Schedule for Compound A35

Dosing of Compound A35 is done on a continuous dosing schedule (CS) oran intermittent dosing schedule (IS). On an IS, patients take 60 mgadministered once a day on 7 consecutive days followed by 21 dayswithout therapy, with cycles repeated every 28 days. On a CS, patientstake 60 mg/day for the entirety of a 28 day cycle. All patients arestarted on a CS dosing regimen. Patients who complete two cycles of CSare switched to the IS.

In all cases, the dosing of rituximab is 375 mg/m2, administered for atotal of 8 doses in 6 months.

Results

On the CS of Compound A35, a response was reported in 7 of 10 patients(70%) with indolent non-Hodgkin's lymphoma (NHL), 9 patients with FL and1 patient with MZL. Only 1 patient had disease progression anddiscontinued from the study. For the other 9 patients, the medianfollow-up is 5.4 months (range, 3.3-7.7 months). Compound A35 incombination with rituximab achieves a very high rate of response inpatients.

A response was reported in 1 of 4 patients (25%) with DLBCL. The patientwho achieved a disease response has been on study for 5.4 months and theother 3 patients were discontinued due to disease progression.

Switch to the IS after 2 Cycles on the CS

15 patients were treated with a regimen consisting of rituximab 375mg/m²×8 doses over 6 months and Compound A35 at 60 mg on the CS for 2cycles then switching to the IS.

To date 10/15 patients have completed 2 cycles on the CS and wereswitched to the IS, and only 1/10 patients (10%) developed delayedimmune-related toxicity with a median follow-up of 3.4 months (range,1.5-5.7) on the IS.

Of the 8 patients who achieved a disease response after 2 cycles oftherapy, none had disease progression on the IS, with a median follow-upof 5.2 months (range, 3.1-7.5) from enrollment.

Compound A35 in combination with rituximab achieves a very high rate ofresponse in patients with relapsed indolent NHL and CLL/SLL. Theseresponses appear durable. These results compare favorably to othertreatment approaches in these disease. Preliminary data suggest that theIS appears to reduce the incidence of delayed onset immune toxicitieswithout erosion in treatment efficacy.

What is claimed is:
 1. A method for treating a hematological malignancy,comprising administering: (i) an effective amount of a compound ofFormula (I);

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein: X, Y,and Z are each independently N or CR^(X), with the proviso that at leasttwo of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen or C₁₋₆alkyl; R¹ and R² are each independently (a) hydrogen, cyano, halo, ornitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(C)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl; R³ and R⁴ areeach independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ are linkedtogether to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆alkenylene, or C₂₋₆ heteroalkenylene; R^(5a) is (a) hydrogen or halo;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R^(5b) is (a) halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R^(5c) is—(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or —(CR^(5f)R^(5g))_(n)-heteroaryl;R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R^(5f) and R^(5g) are eachindependently (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl; R⁶ is hydrogen,C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or —SO₂—C₁₋₆ alkyl; m is 0or 1; and n is 0, 1, 2, 3, or 4; wherein each alkyl, alkylene,heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl,cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R¹, R², R³,R⁴, R⁶, R^(X), R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b), R^(5c),R^(5d), R^(5e), R^(5f), and R^(5g) is optionally substituted with one,two, three, four, or five substituents Q, wherein each substituent Q isindependently selected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each of which is further optionallysubstituted with one, two, three, or four, substituents Q^(a); or (iii)R^(b) and R^(c) together with the N atom to which they are attached formheterocyclyl, which is further optionally substituted with one, two,three, or four, substituents Q^(a); wherein each Q^(a) is independentlyselected from the group consisting of (a) oxo, cyano, halo, and nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g),—NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heterocyclyl; wherein two substituents Q that areadjacent to each other optionally form a C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one, two,three, or four substituents Q^(a); and (ii) an effective amount of aCD20 inhibitor to a patient in need thereof.
 2. The method of claim 1,wherein R^(5b) are each independently (a) halo; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 3. The method of claim 1,wherein R^(5a) and R^(5b) are each independently (a) halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 4. The method of claim 3,wherein R^(5a) and R^(5b) are each methyl, optionally substituted withone, two, or three halos.
 5. The method of claim 4, wherein n is 1, m is0, and R^(5f) and R^(5g) are each hydrogen.
 6. The method of claim 1,wherein the compound of Formula (I) is of Formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein: R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) are each independently (a) hydrogen,cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, eachof which is optionally substituted with one, two, three, or foursubstituents Q^(a); or (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), or —S(O)₂NR^(b)R^(c); or two of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) that are adjacent to each other form C₃₋₁₀cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each optionallysubstituted with one, two, three, or four substituents Q^(a).
 7. Themethod of claim 1, wherein the compound of Formula (I) is selected fromthe group consisting of:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 8. The method of claim 1, whereinthe compound of Formula (I) is Compound A35:

or an isotopic variant thereof, a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.
 9. The method of claim 1, whereinthe CD20 inhibitor is ofatumumab, obinutuzumab, rituximab, ocaratuzumab,ocrelizumab, tositumomab, ibritumomab tiuxetan, tisotumab vedotin,ublituximab, TRU-015, veltuzumab, BTCT4465A (RG7828), EDC9, MT-3724, ora variant or biosimilar thereof, or combinations thereof.
 10. The methodof claim 9, wherein the CD20 inhibitor is rituximab or a variant orbiosimilar thereof.
 11. The method of claim 1, wherein the hematologicalmalignancy is a B-cell malignancy.
 12. The method of claim 11, whereinthe B-cell malignancy is selected from chronic lymphocytic leukemia(CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL),marginal zone B cell lymphoma (MZL), diffuse large B-cell lymphoma(DLBCL), and high grade non-Hodgkin's lymphoma.
 13. The method of claim11, wherein the B-cell malignancy is selected from chronic lymphocyticleukemia (CLL), follicular lymphoma (FL), marginal zone B cell lymphoma(MZL), or diffuse large B-cell lymphoma (DLBCL).
 14. The method of claim1, wherein the cancer is relapsed B-cell non-Hodgkin's lymphoma (NHL) orchronic lymphocytic leukemia (CLL).
 15. The method of claim 1, whereinabout 60 mg/day of the compound of Formula (I), or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof, is administered to the subject.16. The method of claim 15, wherein the method comprises an intermittentdosing schedule (IS), comprising administering to subject the compoundof Formula (I), or an enantiomer, a mixture of enantiomers, a mixture oftwo or more diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofonce daily for 7 consecutive days followed by 21 days without treatmentin a 28-day cycle.
 17. The method of claim 7, further comprisingadministering an effective amount of cyclophosphamide, doxorubicin,vincristine, prednisolone, or a combination thereof.
 18. The method ofclaim 17, wherein the hematological malignancy is diffuse large B-celllymphoma (DLBCL) or follicular lymphoma (FL).
 19. The method of claim 1,wherein the hematological malignancy is a relapsed or refractory B-cellmalignancy.